application/pdf J. Biol. (Downloaded from )Tj Chem. (Kian-Huat Lim and Louis M. Staudt)Tj We further explored downstream effectors of the ERK1/2 signaling in MCF-7 cells. ET AKR1B10 is upregulated in human breast cancer and correlates with tumor size and lymph node metastasis [31], but the underlying molecular mechanisms are unclear. Metabotropic signaling with G-protein coupling. 257:78477851, 1982. 2022 Feb 24;12:727505. doi: 10.3389/fonc.2022.727505. )Tj An aliquot (10 l) of extracts was subjected to radioactivity measurements to determine the total fatty acid synthesis. ET (Alexandra C. Newton, Martin D. Bootman and John D. Scott)Tj (B) Raf/MER/ERK activation by AKR1B10, showing p-Raf, p-MEK and p-ERK1/2 levels in the MCF-7 with ectopic expression of AKR1B10 and BT-20 cells with silencing of AKR1B10. At indicated time points, cells were trypsinized, stained with trypan blue and counted by a Vi-cell counter (Beckman coulter, CA). 3Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, and Departments of Oncologic Sciences and Chemistry, University of South Florida, 12902 Magnolia Drive, Tampa, Florida 33612-9416, United States. ET G-protein coupled receptors (GPCRs) and tyrosine kinase receptors (TKRs) are important upstream activators of lipid second messengers. sharing sensitive information, make sure youre on a federal Thus we further observed the effect of AKR1B10 on proliferation and tumorigenesis of breast cancer cells. 10 0 0 10 60 311 Tm (A) Inhibition of MCF-7 cell proliferation by MEK inhibitors, PD98059 and U0126 at 10 M or 20 M. J. Biol. Federal government websites often end in .gov or .mil. A scrambled siRNA with random RNA sequences was used as a control. /T1_1 1 Tf It is noteworthy to note that AKR1B10 can promote cell survival through protection from reactive carbonyl lesions [13,17,37]. This process is experimental and the keywords may be updated as the learning algorithm improves. 10 0 0 10 60 461 Tm U0126 and PD98059 are MEK1/2 inhibitors that inhibit ERK1/2 signaling activity. Q Interestingly, this study found that aldo-keto reductase 1B10 is a novel regulator of intracellular lipid messengers. More importantly, membrane phospholipids are a major group of lipid second messengers, mediating cellular signaling pathways of cancer cell growth and proliferation [1]. However, little is known of the molecular mechanisms of action. Nishinaka T, Miura T, Sakou M, Hidaka C, Sasaoka C, Okamura A, Okamoto A, Terada T. Chem Biol Interact. BT <>/ProcSet[/PDF/Text/ImageC]/XObject<>>>/Type/Page>> After being air-dried, plates were developed in hexane/diethyl ether/acetic acid (70/30/1, v/v) to separate neutral lipids, such as DAG, or in chloroform/methanol/acetic acid (65/25/10, v/v) to separate phospholipids, such as PIP2 and IP3. Am. BT AKR1B10 is an oncoprotein that promotes growth and progression of breast cancer. <>stream 7). 10 0 0 10 50 529 Tm Figure 1.. AKR1B10 promotes lipogenesis of cancer cells. (2016; doi: 10.1101/cshperspect.a005926)Tj Authors A F Quest 1 , S Ghosh , W Q Xie , R M Bell Affiliation 1 Department of Molecular Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. 2B). 468 0 0 60 72 126 cm and PAF increased phospholipase C activity. ET <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/Properties<>>>/Rotate 0/Type/Page>> ET Martin HJ, Breyer-Pfaff U, Wsol V, Venz S, Block S, Maser E. Purification and characterization of akr1b10 from human liver: role in carbonyl reduction of xenobiotics, Drug metabolism and disposition: the biological fate of chemicals, Aldo-keto reductase family 1 B10 affects fatty acid synthesis by regulating the stability of acetyl-CoA carboxylase-alpha in breast cancer cells, Increased lipogenesis in cancer cells: new players, novel targets, Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis, Overexpression and oncogenic function of aldo-keto reductase family 1B10 (AKR1B10) in pancreatic carcinoma, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. Fukumoto S, Yamauchi N, Moriguchi H /T1_0 1 Tf The CYS2 region of PKC-gamma (amino acids 92173) expressed as a COOH-terminal fusion protein with glutathione-S-transferase (GST-Cys2) displayed high-affinity, stereospecific, and phospholipid dependent binding to phorbol ester and contained 2 moles of zinc per mole protein. 0 0 1 rg As shown in Fig. An aliquot (10 l) of the cell suspension was used for protein quantitation, and the remainder was mixed vigorously with 20 volumes of chloroform/ methanol (2:1, v/v). Imaging times were controlled equally at 15 sec, and signal quantification was performed by an acquisition and analysis software (Living ImageVR, Xenogen, CA) and expressed as amount of Flux (photons per second). ET Together with diacylglycerol (DAG), IP3is a second messenger molecule used in signal transduction in biological cells. endobj House, C. and Kemp, B.E. /T1_2 1 Tf (In Press), Quest, A.F.G. 10 0 0 10 50 423 Tm AKR1B10 promotes lipogenesis and enhances cellular PIP2, DAG and IP3 levels. DAG is an activator of protein kinase C (PKC) family members [9]. endobj 10 0 0 10 308 378.99997 Tm Chem. Acad. Oncotarget. BT ET BT Part of Springer Nature. -1 TL /Im1 Do Increased PIP2 and IP3 levels in breast cancer cells encouraged an extended study on DAG and the DAG-mediated signaling transduction. The .gov means its official. <>stream Proc., Fed. H1nga_`y\@,vm\X,lx 7)"+v\x )(o$"TP)P{ Ah(%vy oQ y ?NA|gJr:7[| c~9dYx}mZ`[ )hn~S* izAht:1g)E.%}{r|:Wp &=8& Natl. /T1_2 1 Tf 2022 Springer Nature Switzerland AG. AKR1B10 is not expressed in normal breast, but up-regulated in breast cancer, indicating a poor prognosis. -8.11398 0 Td (A) PKC activation by AKR1B10, showing p-PKC (Thr505), p-PKC (Ser744/748) and p-PKC/II (Thr638/641) levels in the MCF-7 with ectopic expression of AKR1B10 and BT-20 cells with silencing of AKR1B10. 1Department of Medical Microbiology, Immunology & Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine. 148 0 obj <> will also be available for a limited time. The organic phase was collected and dried by speed vacuum. T* Various in vitro assays for enzymes involved in arachidonic acid release and metabolism were conducted. 10 0 0 10 242.84967 212 Tm Am J Physiol. (A) Total DAG levels in MCF-7 cells with AKR1B10 expression (left) and BT-20 cells and HCT-8 cells with AKR1B10 silencing (right). Exp. BT These results suggest that the inability of AII to maintain tension, unlike PE, is due to its inability to produce DAG continuously and activate protein kinase C. Insulin, concanavalin A, EGF, IFG-I and vanadate activate de novo phosphatidic acid and diacylglycerol synthesis, C-kinase, and glucose transport in BC3H-1 myocytes, Mechanism for release of arachidonic acid during guinea pig platelet aggregation: a role for the diacylglycerol lipase inhibitor RHC 80267, Substrate selectivity of diacylglycerol kinase in PDGF-stimulated 3T3 cells, Hypersensitivity of phospholipase C in platelets of spontaneously hypertensive rats, Evidence for a requirement of agonist-induced diacylglycerol production during tonic contraction of rat aorta. /T1_2 1 Tf (C) ERK inhibition by a broad PKC inhibitor, Go6893 (10M), showing decreased p-ERK1/2 level by Go6893 in the MCF-7 cells with AKR1B10 expression. RHC 80267, a diacylglycerol lipase inhibitor, and indomethacin, a cyclooxygenase inhibitor, were used. %PDF-1.4 % 2021 Aug 21;11(1):163. doi: 10.1186/s13578-021-00677-3. ET MCF-7, BT-20, HCT-8 and 293T cells purchased from American Type Culture Collection (ATCC, VA) were maintained in indicated medium at 37C, 5% CO2. Long chain fatty acids are important components of membrane phospholipids and lipid second messengers which mediate cellular signaling transduction and thus cell survival and proliferation [5-7]. BT Acrobat Distiller 11.0 (Windows) This result was confirmed by both Alamar blue (Fig. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. (Sally Kornbluth and Rafael Fissore)Tj Search terms: Advanced search options. Acini were photographed by a phase contrast microscopy (Carl Zeiss, CA). BT In unstimulated cells, both the rate and extent of /sup 32/P incorporation into individual inositol-containing phospholipids and phosphatidic acid were identical in SHR and WKY. Platelets were labeled with (/sup 14/C)arachidonic acid to facilitate sensitive determination of small changes in platelet phospholipids during platelet aggregation. ET Two analogs were potent inhibitors in vitro, 1-monooleoylglycerol(MOG,K/sub I/ = 91 ..mu..M) and diotanoylethyleneglycol (diC/sub 8/EG, K/sub I/ = 58 ..mu..M). It was observed that cyclooxygenase products were responsible for collagen-induced guinea pig platelet aggregation. Google Scholar. Diacylglycerol (DAG) and subspecies were quantitatively and qualitatively detected by LC-MS through Washington University Mass Spec Facility. In this study, the authors have compared the effects of concanavalin A, EGF, IGF-I and sodium orthovanadate to insulin on PA/DG synthesis, C-kinase activity and glucose transport. endobj /T1_1 1 Tf 0 g Ahmed, S., Kozma, R., Lee, J., Monfries, C., Harden, N. and Louis, L. Biochem. These lipid second messengers activate PKC and thus the PKC-mediated ERK signaling cascade, promoting growth and proliferation of breast cancer cells (Fig. Q ET Acad. and Bell, R.M. 2016 Jul 12;7(28):43779-43791. doi: 10.18632/oncotarget.9672. Tumor volume was monitored by both in vivo imaging and caliper measurements. Clark, J.D., Lim, L.L., Kriz, R.W., Ramesha, C.S., Sultzman, L.A., Lin, A.Y., Milona, L. and Knopf, J. L. Cell 65:10431051, 1991. Keywords: Dag Second Messengers: Molecular Switches and Growth Control. On the other hand, RHC 80267 was a powerful inhibitor of aggregation and ADP release induced by all three of these potent aggregating agents. Sun Y, Liu WZ, Liu T, Feng X, Yang N, Zhou HF. Figure 1.. AKR1B10 promotes lipogenesis of cancer. In breast cancer, AKR1B10 is upregulated in ductal carcinoma in situ (DCIS) and invasive, metastatic and recurrent tumors and correlates with tumor size, lymph node metastasis, and disease-related death. With PDGF treatment, the radioactivity in endogenous PA increased fourfold, whereas the radioactivity in PA/sub, Thrombin-induced aggregation and serotonin release were markedly enhanced in platelets from spontaneously hypertensive rats (SHR) when compared with those from normotensive Wistar-Kyoto rats (WKY). Federal government websites often end in .gov or .mil. 10 0 0 10 60 413 Tm 1A). Moreover, the extent of the difference between SHR and WKY was independent of the extracellular calcium concentration. Medium was added with 1/10 (v/v) Alamar blue and changed regularly every 24hr. AKR1B10 expression and lipid synthesis in the MCF-7 (A), BT-20 (B) and HCT-8 (C) cells. AKR1B10 is a novel oncogenic protein in breast cancer. In contrast, early thrombin-induced phosphoinositide metabolism, when, A possible role for protein kinase C during the tonic phase of arterial contraction was examined in rat aorta by observing the effects of the phorbol ester, 12-0-tetradecanoylphorbol-13-acetate (TPA), on angiotensin II (AII)-induced responses. protein kinase c isozymes are stereospecifically regulated by diacylglycerol (dag) second messengers or phorbol esters (pdbu) through interactions with cysteine-rich pkc segments (cysl, cys2) containing six conserved cysteines (c) and two conserved histidines (h) in the pattern h-x 12 -c-x 10-14 -c-x 2 -c-x 4 -h-x 2 -c-x 7 -c where x are The minimal sequence required for PDBu binding was elucidated by deletion analysis. Yan R, Zu X, Ma J, Liu Z, Adeyanju M, Cao D. Aldo-keto reductase family 1 B10 gene silencing results in growth inhibition of colorectal cancer cells: Implication for cancer intervention, Separation of phosphatidylinositols and other phospholipids by two-step one-dimensional thin-layer chromatography. 550201* - Biochemistry- Tracer Techniques, - Fed. In these cells, phospho-p90RSK, phospho-MSK, and Cyclin D1 expression was increased by AKR1B10, and pharmacological inhibition of the ERK signaling cascade with MEK1/2 inhibitors U0126 and PD98059 eradicated induction of phospho-p90RSK, phospho-MSK, and Cyclin D1. We next tested if the ERK1/2 signaling activation is responsible for increased cell proliferation by AKR1B10. second messenger, molecule inside cells that acts to transmit signals from a receptor to a target. 10 0 0 10 318 508.99997 Tm Figure 3.. AKR1B10 activates PKC/ERK signaling pathway. ( on December 11, 2022 - Published by Cold Spring Harbor Laboratory Press\ )Tj An official website of the United States government. AKR1B10 also mediates cancer cell sensitivity to anthracyclines [24,25]. The QC was injected seven times at the beginning to stabilize the instrument, and was injected again every five study samples. Huang C, Verhulst S, Shen Y, Bu Y, Cao Y, He Y, Wang Y, Huang D, Cai C, Rao K, Liao DF, Jin J, Cao D. Oncotarget. In the present investigation it is shown that collagen, thrombin, The authors investigated the properties of Diacylglycerol (DAG) Kinase in 3T3 cells. MOG treatment elevated DAG levels up to 4-fold in unstimulated platelets. Kolch, W., Heidecker, G., Lloyd, P. and Rapp, U. These results provide evidence for a leftward shift of the dose-response and time-course curves of thrombin-induced (/sup 32/P)phosphatidic acid formation in SHR. AKR1B10 increases fatty acid synthesis by stabilizing ACCA, enhancing cellular phospholipids and sterols. ET 6, MCF-7 tumors with AKR1B10 expression grew faster than vector control tumors. Signal transduction in vascular smooth muscle: diacylglycerol second messengers and PKC action. Clipboard, Search History, and several other advanced features are temporarily unavailable. ET For 2D culture, cells were seeded at 200 cells per 60-mm culture dish and incubated in indicated medium for 14 days; colonies were fixed by methanol (cooled at 20C) for 10 min and visualized by 0.1% crystal violet. GST-fusion proteins containing this region of raf-1 contained two moles of zinc but did not bind PDBu. Qualitative analyses by liquid chromatography-mass spectrum (LC-MS) revealed that AKR1B10 regulated the cellular levels of total DAG and majority of subspecies. *, p<0.05 and **, p<0.01 when compared to vector control. <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/Properties<>>>/Rotate 0/Type/Page>> PKD at the crossroads of DAG and PKC signaling. A pan inhibitor of PKC (Go6983) blocked ERK1/2 activation by AKR1B10. Zeman RJ, Wen X, Ouyang N, Brown AM, Etlinger JD. Q: A protein contained in red blood cells is . (Doreen Cantrell)Tj /T1_2 1 Tf /T1_1 1 Tf 10 0 0 10 50 495 Tm Activated ERK1/2 phosphorylates several substrates, including p90RSK and MSK. In: Honn, K.V., Nigam, S., Marnett, L.J. Quality control (QC) samples were prepared by pooling the aliquots of study samples and were used to monitor instrument stability. Exton, J.H. 2022-12-11T18:18:39-08:00 further insights into the regulation of DAG second messengers. 0 1 TD BT Tel: (314) 747-0677. ET The guinea pig platelet is an ideal model to study phospholipase C-diacylglycerol lipase pathway for the release of arachidonic acid from platelet phospholipids because it does not have any phospholipase A/sub 2/ activity. 2015 Jun 5;234:274-81. doi: 10.1016/j.cbi.2014.11.013. Phosphoinositide 3-kinase (PI3K) and phospholipase C (PLC) are two major mediators of cellular lipid messengers. In the breast cancer cells, AKR1B10 promotes lipogenesis and increases cellular lipid second messengers PIP2, IP3 and DAG, which activates the PKC/ERK signaling cascade. In vivo studies in immunodeficient female nude mice confirmed the tumor-promoting role of AKR1B10 in breast cancer. Therefore, AKR1B10 may activate lipid second messenger-mediated signaling cascades to affect growth and proliferation of breast cancer cells. uuid:79068d31-c36f-4e54-9b1e-32efcd71848f (C) Acinar formation and growth of MCF-7 cells in the Matrigel-based 3D culture. We further assessed the effect of AKR1B10 on clonogenic growth of MCF-7 cells in three-dimensional (3D) culture in growth factor-reduced extracellular matrix that mimics in vivo environment of mammary epithelial cells. It functions as a second messenger that facilitates the protein kinase C (PKC) enzyme's movement from the . (Protein Regulation in Signal Transduction)Tj BT Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis, Journal of receptor and signal transduction research. Diacylglycerol (DAG) and subspecies were quantitatively and qualitatively detected by LC-MS through Washington University Mass Spec Facility. /T1_2 1 Tf 913 N. Rutledge Street, Springfield, IL 62794. Neurotrauma Rep. 2021 Sep 14;2(1):411-423. doi: 10.1089/neur.2021.0018. (Michael J. Lee and Michael B. Yaffe)Tj Relative quantification data generated in same batches are appropriate to compare the change of an analyte in AKR1B10 expression or AKR1B10 silencing samples to the corresponding control. BT Figure 7.. Hypothetic model of cell growth and proliferation promoted by AKR1B10. We thus assessed the effect of targeted AKR1B10 expression on growth and proliferation of breast cancer cells. 3-phosphoinositide-dependent protein kinase-1 regulates proliferation and survival of cancer cells with an activated mitogen-activated protein kinase pathway, Sustained MAP kinase activation is required for the expression of cyclin D1, p21Cip1 and a subset of AP-1 proteins in CCL39 cells. Qu J, Li J, Zhang Y, He R, Liu X, Gong K, Duan L, Luo W, Hu Z, Wang G, Xia C, Luo D. Cell Biosci. /T1_1 1 Tf PDBu binding was decreased substantially upon removal of Val147 and lost entirely when Val144 was deleted. Our data showed that ectopic expression of AKR1B10 in breast cancer cells MCF-7 promoted lipogenesis and enhanced levels of lipid second messengers, including phosphatidylinositol bisphosphate (PIP2), diacylglycerol (DAG) and inositol triphosphate (IP3). DAG and subspecies were measured quantitatively by liquid chromatography-mass spectrum as described in Methods and Materials. DAG activates protein kinase C and IP3 binds to a receptor on the endoplasmic reticulum to release calcium from intracellular stores. Figure 4.. AKR1B10 promotes growth and proliferation. BT 10 0 0 10 318 311 Tm Diacylglycerol (DAG) is composed of two chains of fatty acids that are in a covalent bond with a molecule of glycerol. T* Smith, M.R., DeGudicibus, S.J. Together these data suggest that in breast cancer cells, AKR1B10 promotes lipogenesis and increases the cellular levels of important lipid second messengers, PIP2, IP3 and DAG. ET This is a preview of subscription content, access via your institution. A: Joints can be outlined as the point where two parts of the skeletal system are associated with each . cAMP, cGMP, IP3, DAG. /T1_2 1 Tf <> 10 0 0 10 308 529 Tm 0 g ET INTRODUCTION Second messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell. (C) Caliper measurements of the tumor size. Lipogenesis is increased in tumors and contributes to various aspects of tumorigenesis and progression, such as cell proliferation, differentiation and invasion [1,4]. Cells were pulsed with 1Ci of [2-14C] acetate (53 mCi/mmol; Amersham Biosciences) per well of 12-well plates for 4h at 37 C, 5% CO2 in complete medium. At least two pathways may contribute to the attenuation of the DAG signal: (1) phosphorylation to phosphatidic acid(PA) by DAG kinase(DGK), and (2) deacylation by DAG and monoacylglycerol lipases. 266:32153221, 1991. ET Phospholipids are essential components of bio-membranes and important second messengers in cellular signaling transduction, regulating various pathophysiological processes [1-3]. 280:233241, 1991. -14.28398 0 Td It was also discovered that cyclooxygenase products were responsible for further stimulation (a positive feed-back) of phospholipase C activity, while diacylglycerol provided a negative feed-back control over receptor-stimulated phospholipase C activity and inhibited ADP release. government site. PubMedGoogle Scholar, Wayne State University, Detroit, Michigan, USA, Vanderbilt University, Nashville, Tennessee, USA, 1997 Springer Science+Business Media New York, Quest, A.F., Ghosh, S., Xie, W.Q., Bell, R.M. BT endobj 1C). total glycerolipids, although none were as effective as insulin, which increased (/sup 3/H)DG 400% in 1 minute. Overexpression of the aldo-keto reductase family protein AKR1B10 is highly correlated with smokers' non-small cell lung carcinomas, Clinical cancer research : an official journal of the American Association for Cancer Research, AKR1B10 overexpression in breast cancer: association with tumor size, lymph node metastasis and patient survival and its potential as a novel serum marker, Epidermal growth factor induces tumour marker AKR1B10 expression through activator protein-1 signalling in hepatocellular carcinoma cells, AKR1B10 promotes breast cancer metastasis through integrin alpha5/delta-catenin mediated FAK/Src/Rac1 signaling pathway. Proc. DiC/sub 10/ was added to the cell medium before harvesting. **, p<0.01 when compared to the vector control or PD98059/U0126-treated cells. J. Although repetitive observations were not conducted in these breast cancer cells with targeted expression or silencing of AKR1B10, we believe that the carbonyl detoxification mechanism of AKR1B10 may also contribute to the cell growth and proliferation. 10 0 0 10 50 447 Tm /T1_1 1 Tf DAG activates important oncogenic signaling molecule PKC, and IP3 provokes ER-mediated calcium signaling, further activating PKC. These data suggest that AKR1B10 promotes breast cancer growth in vivo by activating the PKC/ERK signaling pathway, being an oncogenic protein in breast cancer growth and progression. As shown in Fig. 10 0 0 10 318 403 Tm 226 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/Properties<>>>/Rotate 0/Type/Page>> 1994 Sep;267(3 Pt 1):C659-78. 0 0 m Herein we report that AKR1B10 activates lipid second messengers to stimulate cell proliferation. In contrast, phosphorylation of these PKC isoforms decreased in BT-20 cells with AKR1B10 silencing by two different siRNAs that target different regions of mRNA. Briefly, after being washed with PBS, cells were harvested by trypsinization and suspended in 40 l of PBS. In breast cancer cells, AKR1B10 promoted the clonogenic growth and proliferation of breast cancer cells in two-dimension (2D) and three-dimension (3D) cultures and tumor growth in immunodeficient female nude mice through activation of the PKC/ERK pathway. Briefly, MCF-7 cells (3,000 cells/well) were plated in 96-well plates. The second messenger pathway which concerns the intracellular action of Ca2+ ions is involved in a variety of actions that include the collaboration with DAG for the activation of PKC and the calcium-modulated protein (calmodulin or Cam) kinase pathway. Therefore, we examined phosphorylation activation of PKC isoforms. Role of the Polyol Pathway in Locomotor Recovery and Wallerian Degeneration after Spinal Cord Contusion Injury. Quest, A.F.G., Bioomenthal, J.B., Bardes, E.S.G. Trends Pharmacol Sci. Relative quantification of lipids was provided, and data were reported as the peak area ratios of the analytes to the internal standard. However, little is known of the molecular mechanisms of action. 562 568 l DC and JJ worked in all aspects of the project and revised the manuscript. /T1_1 1 Tf Hubbard, S.R., Bishop, W.R., Kirschmeier, P., George, S.J., Cramer, S.P. 10 0 0 10 413.50934 345 Tm Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr. Cellular fatty acid metabolism and cancer, Metabolic pathways promoting cancer cell survival and growth, Membrane lipids: where they are and how they behave, Phosphoinositide lipid second messengers: new paradigms for transepithelial signal transduction, Pflugers Archiv : European journal of physiology, Protein kinase C (PKC) family in cancer progression, Protein kinase C and other diacylglycerol effectors in cancer, MAPK signal pathways in the regulation of cell proliferation in mammalian cells, Identification and characterization of a novel human aldose reductase-like gene, Substrate specificity and catalytic efficiency of aldo-keto reductases with phospholipid aldehydes, Aldo-keto reductase family 1 B10 protein detoxifies dietary and lipid-derived alpha, beta-unsaturated carbonyls at physiological levels, Biochemical and biophysical research communications, Human aldo-keto reductases 1B1 and 1B10: A comparative study on their enzyme activity toward electrophilic carbonyl compounds. Accessibility 562 96 l (Mary B. Kennedy)Tj 2Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (incubation), Hunan University of Chinese Medicine, Changsha, Hunan 410208, China. Bums, D.J. In the center, binding of ligands to a GPCR (receptor) activates phospholipase C (PLC; the effector), to generate two second messengers, DAG and IP 3, which activate protein kinase C (PKC; the target) and release calcium from intracellular stores, respectively. In 2D plating efficiency assays, the colony formation rate of MCF-7 cells with AKR1B10 expression was at an average of 78.04.8% (n=3), compared to 56.01.6% in the vector control cells. (A) Proliferation of MCF-7 and BT-20 cells measured by Alamar blue assays (left) and cell counting assays (right). Luciferase-labelled MCF-7 cells with targeted AKR1B10 expression or a vector control were injected subcutaneously into the mammary fat pads of female nude mice (n=5 per group). /T1_0 1 Tf Down-regulation of aldo-keto reductase AKR1B10 gene expression by a phorbol ester via the ERK/c-Jun signaling pathway. Our data showed that ectopic expression of AKR1B10 in breast cancer cells MCF-7 promoted lipogenesis and enhanced levels of lipid second messengers, including phosphatidylinositol bisphosphate (PIP2), diacylglycerol (DAG), and inositol triphosphate (IP3). 194 0 obj 10 0 0 10 318 461 Tm BT government site. Careers, The publisher's final edited version of this article is available at, GUID:E2FCDCBA-1036-4140-99CD-716FC3170795, AKR1B10, breast cancer, lipid second messengers, phosphatidylinositol bisphosphate, diacylglycerol, PKC/ERK cascade, Cancer Metabolism: A Modeling Perspective, Signal transduction through lipid second messengers. Protein lysates, SDS-PAGE and Western blotting were performed as previously described [26]. (Synaptic Signaling in Learning and Memory)Tj 2022-12-11T18:18:39-08:00 To verify that the PDGF effect on PA/sub 10/ formation in intact cells was due to reduced phosphorylation of diC/sub 10/ by DAG kinase, cells were treated with PDGF and/or diC/sub 10/, freeze-thawed, and then incubated with Mg(/sup 32/P)ATP. 0 1.00001 TD AKR1B10 knockdown was examined using Western blot. 265:14, 1990. (Signal Transduction)Tj Li W, Wang X, Zhang X, Gong P, Ding D, Wang N, Wang Z. Lipids Health Dis. Oppositely, silencing of AKR1B10 in BT-20 cells led to decrease in total lipids, PIP2 and IP3 (Fig. Cells (4000/well) were seeded. (Douglas R. Green and Fabien Llambi)Tj Unable to display preview. /T1_1 1 Tf (\240)Tj Lipid samples and standards were visualized by coloration in staining solution (0.12 M NaCl, 20% methanol, and 300 mg/liter Coomassie Blue). CAS (Signaling Networks that Regulate Cell Migration)Tj 2022 Aug 26;8(1):374. doi: 10.1038/s41420-022-01135-w. Cao Z, Delfino K, Tiwari V, Wang X, Hannan A, Zaidi F, McClintock A, Robinson K, Zhu Y, Gao J, Cao D, Rao K. Front Oncol. 10 0 0 10 308 447 Tm The rest of author panel assisted in animal welfare, experimental preparation, literature search, and data analysis or provided advices in the project design. T* Herein we found that AKR1B10 activates the cellular lipid second messengers and thus triggers the lipid-mediated cell proliferative signal transduction. Aldo-keto reductase 1B10 (AKR1B10), also referred as aldose reductase-like-1 (ARL-1) [11], is a monomeric enzyme with strong catalytic activity to , -unsaturated carbonyl compounds [12-14] and protects the host cells from carbonyl lesions [15-17]. HHS Vulnerability Disclosure, Help official website and that any information you provide is encrypted IS, internal standard. (Computation, and Decision Making)Tj This in turn modulated the phosphorylation of protein kinase C (PKC) isoforms PKC (Thr505), PKC (Ser744/748) and PKC/II (Thr638/641) and activity of the PKC-mediated c-Raf/MEK/ERK signaling cascade. (D. Scott)Tj <> Biol. (al. Second Messengers about navigating our updated article layout. J. Biol. Protein kinase C isozymes are stereospecifically regulated by diacylglycerol (DAG) second messengers or phorbol esters (PDBu) through interactions with cysteine-rich PKC segments (Cysl, Cys2) containing six conserved cysteines (C) and two conserved histidines (H) in the pattern H-X12-C-X1014-C-X2-C-X4-H-X2-C-X7-C where X are non-conserved residues. S <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/Properties<>>>/Rotate 0/Type/Page>> endobj (D) PKC/ERK signaling activity in tumors. /T1_2 1 Tf Chem. (A) Inhibition of MCF-7 cell proliferation by MEK inhibitors, PD98059 and U0126 at 10 M or 20 M. /T1_2 1 Tf Left panel: Quantitative analysis of band intensity. Chem 261:93419347, 1986. AII (5 x 10/sup -7/M) causes only a transient contractile response, while PE (10/sup -5/M) causes a sustained tonic contraction. ET Y axis is in log10. /T1_2 1 Tf Biol. The results showed that ectopic expression of AKR1B10 promoted clonogenic growth in both 2D and 3D cultures and tumorigenesis in nude mice, but silencing of AKR1B10 suppressed growth and proliferation of breast cancer cells. 5 and 10 min while PE was able to do so, indicating the failure of AII to provide DAG to sustain protein kinase C activation. Figure 3.. AKR1B10 activates PKC/ERK signaling pathway in breast cancer cells. 130 0 obj IS, internal standard. 10 0 0 10 60 519 Tm -8.83699 0 Td /T1_0 1 Tf (Subversion of Cell Signaling by Pathogens)Tj They are a component of cell signaling pathways. AKR1B10 promotes breast cancer cell proliferation and migration via the PI3K/AKT/NF-B signaling pathway. 4B). **, p<0.01 when compared to AKR1B10 Control cells. Figure 5.. ERK signaling and target genes, Figure 5.. ERK signaling and target genes that are involved in cell proliferation enhanced by, Figure 6.. AKR1B10 promotes tumor growth in. https://doi.org/10.1007/978-1-4615-5325-0_42, Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury 2, Advances in Experimental Medicine and Biology, Shipping restrictions may apply, check to see if you are impacted, Tax calculation will be finalised during checkout. luciferase substrate D-luciferin at 100 mg/kg in PBS and anesthetized by isoflurane. (B) Plating efficiency of MCF-7 cells in cell culture dishes. endobj (Signal Transduction: From the Atomic Age to the)Tj The beta isozymes of PLC are regulated by G-proteins (G-alphaq/11 and G-betagamma) Berridge (1989), Gilman (1989). (In Press), Quest, A.F.G., Bardes, E.S.G. 10 0 0 10 308 495 Tm They examined effects of concanavalin A and EGF on C-kinase activity and found that both agonists, like insulin, increase C-kinase activity in cytosolic and/or membrane fractions. Aldo-keto reductase 1B10 (AKR1B10) is upregulated in breast cancer and promotes tumor growth and metastasis. 244 0 obj The p90RSK, MSK and cyclin D1 functions as downstream targets of the ERK1/2 in this process. ERK1/2 is an important oncogenic signaling that regulates cell proliferation and survival [41]. (B) Tumor volumes by in vivo bioluminescence at photon/second. Chem. The colony size of AKR1B10 expression cells was notably larger than that of vector control cells (Fig. and Bell, R.M. /T1_2 1 Tf Download full-text PDF Read full-text. Introduction Diacylglycerol (DAG) is a lipid signal messenger which is an essential second messenger in mammalian cells. ET ERK1/2 also induces cyclin D1 expression through an AP-1 mediated mechanism, stimulating G1/S progression and cell proliferation [10,40]. In studies of the properties of DAG kinase with pure DAGs in mixed detergent micelles, they found that the enzyme phosphorylated arachidonoyl-DAG more readily than diC/sub 10/. (Alexandra C. Newton, Martin D. Bootman and John)Tj (Cell Signaling and Stress Responses)Tj After incubation on ice for 10 min, debris was removed at 21,000 xg for 10 min, and the supernatant was washed with 0.2 volume of distilled water. 3C). *, p<0.05 and **, p<0.01 when compared to AKR1B10 Control cells. *, p<0.05 and **, p<0.01 when compared to vector control. Lipid extracts and appropriate lipid standards (Sigma, MO) were spotted on silica gel (60; Sigma, MO). (Peter Devreotes and Alan Rick Horwitz)Tj AKR1B10 promotes breast cancer metastasis through integrin 5/-catenin mediated FAK/Src/Rac1 signaling pathway. 0 0 1 rg <>/Filter/FlateDecode/Height 300/Length 34147/Name/X/Subtype/Image/Type/XObject/Width 1200>>stream 50 96 m 4China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin, 541001, Guangxi, China. 11 0 0 11 205.27596 579.99988 Tm Tumor volume was measured using in vivo bioluminescent imaging with an IVIS VR imaging system (Xenogen, CA) and also measured by Vernier caliper. Similar to other. MCF-7 cells (5 106) labeled with luciferase were implanted in the mammary fat pads (orthotopic) of immunodeficient female mice at 4-6 weeks old. Mol Carcinog. 10 0 0 10 50 321 Tm right) assays. In brief, lipids were extracted from 510 6 cells using a modified Bligh-Dyer method in the presence of an internal standard DG15:0-15:0 (0.5 g per sample). ( )Tj We have established a novel role for the second messenger DAG (diacylglycerol), a product of PtdIns(4,5)P2 hydrolysis by PLC . 3B, phosphorylated c-Raf, MEK1/2 and ERK1/2 all increased in MCF-7 cells with ectopic expression of AKR1B10, but decreased in BT-20 cells with AKR1B10 knockdown. BT (Signaling in Lymphocyte Activation)Tj AKR1B10 associates with acetyl-CoA carboxylase- (ACCA) and prevents its ubiquitin-dependent degradation [26]. 122 0 obj 2021 Nov 13;20(1):160. doi: 10.1186/s12944-021-01572-z. Left: AKR1B10 mRNA by qRT-PCR, GAPDH mRNA was used as an internal control; middle: AKR1B10 protein by Western blot; and right: Lipogenesis, showing total lipid (T-lipid), PIP2 and IP3 levels influenced by AKR1B10. A pellet of 17-estradiol (0.72mg/pellet) was implanted beneath the neck skin. Mice were placed onto a warm stage inside a light-tight camera box with continuous exposure to isoflurane. The results showed that MCF-7 cells with AKR1B10 expression formed more and larger acini than vector control cells (Fig. (Ivana Y. Kuo and Barbara E. Ehrlich)Tj /T1_1 1 Tf ZOOLOGY 2. This fusion protein translocated to phospholipid vesicles in an phosphatidylserine (PS)-dependent manner. 10 0 0 10 318 358.99997 Tm In fact, AKR1B10 is upregulated in multiple solid cancers, such as liver, breast, lung and pancreatic cancers, being a potential prognostic biomarker [29-32]. Additionally, all activators rapidly increased the incorporation of (/sup 3/H)glycerol into DG and, The mechanism of the release of arachidonic acid from phospholipids after the stimulation of guinea pig platelets with collagen, thrombin and platelet activating factor (PAF) was studied. Epub 2006 May 6. /T1_2 1 Tf (Signaling Pathways that Regulate Cell Division)Tj The ability of AII and phenylephrine (PE) to induce diacylglycerol (DAG) production was monitored as agonist-stimulated /sup 32/P-labelling of phosphatidic acid (PA). endobj This study showed that AKR1B10 promoted clonogenic growth of breast cancer cells by increasing lipogenesis and thus activating lipid second messengers PIP2 and DAG-mediated PKC/ERK signaling cascade. ( Superfamily)Tj Together these data suggest that AKR1B10 promotes clonogenic growth and proliferation of breast cancer cells. The selectivity of DAG kinase may play a key role in the formation of arachidonoyl species of PI. 2016-07-20T11:04:33+05:30 Bookshelf /T1_2 1 Tf *, p<0.05 and **, p<0.01 when compared to vector control. The p90RSK, MSK and cyclin D1 functions as downstream targets of the ERK1/2 in this process. Google Scholar. Arbortext Advanced Print Publisher 9.1.520/W Europe PMC is an archive of life sciences journal literature. (1994) J. Biol. and Bell, R.M. Second Messengers Bioenergetics Investigating Photosynthesis Biological Molecules ATP Carbohydrates Condensation Reaction DNA and RNA DNA replication Denaturation Enzymes Factors Affecting Enzyme Activity Fatty Acids Hydrolysis Reaction Inorganic Ions Lipids Measuring enzyme-controlled reactions Monomers Monomers and Polymers Monosaccharides Acetate incorporation into lipid species, including phosphatidylinositol-4,5-bisphosphate (PIP2), inositol-1,4,5- trisphosphate (IP3) and diacylglycerol (DAG), was analyzed by thin layer chromatography (TLC). By contrast, although the COOH-terminal conserved C-151 was involved in the coordination of 1 zinc atom, it was not essential for PDBu binding. Meth. More impressively, AKR1B10 promoted clonogenic growth of MCF-7 cells, a feature of cancer cells. CAS Neurosci. PubMed PMC legacy view 10/ and PI/sub 10/ was consistently decreased. PubMed Viable cells correlate with the magnitude of Alamar blue reduction (%) following the manufactures instructions. /T1_0 1 Tf A number of DAG analogs were tested as substrates and inhibitors of partially purified pig brain DGK. [251 0 R 252 0 R 253 0 R 254 0 R] PDGF treatment caused an increase in DAG mass, an increase in incorporation of /sup 32/P into phosphatidic acid (PA) and phosphatidylinositol (PI), and an increase in the rate of phosphorylation of membrane DAG in vitro. 8:138153, 1993. P30 CA076292/CA/NCI NIH HHS/United States, P30 DK020579/DK/NIDDK NIH HHS/United States, NCI CPTC Antibody Characterization Program. This has important biological significance as the human beings are constantly exposed to the carbonyls derived from daily diet consumption, microbes inhabited within digestive tract, cellular metabolism and lipid peroxidation in oxidative stress [18-21]. 0 0 m Advances in Experimental Medicine and Biology, vol 400. Science 238:17261728, 1987. BT 562 545 l 8:32353243, 1988. (Signaling in Muscle Contraction)Tj and Buss, J.E. (Cell Death Signaling)Tj /T1_2 1 Tf **, p<0.01 when compared to the vector control or PD98059/U0126-treated cells. DAG and subspecies were measured quantitatively by liquid chromatography-mass spectrum as described in Methods and Materials. Quest, A.F.G., Bardes, E.S.G. and Bell, R.M. Our data showed that ectopic expression of AKR1B10 in breast cancer cells . Second messengers are molecules that relay signals received at receptors on the cell surface such as the arrival of protein hormones, growth factors, etc. Li J, Guo Y, Duan L, Hu X, Zhang X, Hu J, Huang L, He R, Hu Z, Luo W, Tan T, Huang R, Liao D, Zhu YS, Luo DX. U{7>O5HjQZ_= "\^QR)pxZm.DLXgE\sbg WQp1.0pxz-/(kvek0iKp(&i 6=x18mY^+Bo:sAs \=z18=ORo\pN'66ox+k {{x6S.VfzC>9,vek wn$atB}q^/c?t:?uxEEM:M$I89We^ Rfs5vscZ$V1zdtd>^_{ [7nnYgr\3[cyvD d{pnn>^_|jN$a\5nQpqZQ:*:"18p|gcZSp pU\n+~~9GnhZ<17J JJa`$a!~wRP_\p'O:CbiY|[7nj77z( pGQI'Q'D>;irkai.c{;R A AFF1g\z4x}-fsun;\j. ET 267:1019310197, 1992. In the breast cancer cells, AKR1B10 promotes lipogenesis and increases cellular lipid second messengers PIP2, IP3 and DAG, which activates the PKC/ERK signaling cascade. DAG second messengers: molecular switches and growth control Adv Exp Med Biol. q In particular, we quantitatively measured total cellular DAG and all 16 subspecies using LC-MS through the core facility in Washington University at St Louis, and the results strengthened the quality and accuracy of our data. 10 0 0 10 238.36987 554 Tm Cells were prelabeled with /sup 32/P and treated with PDGF or carrier. (G\366khan S. Hotamisligil and Roger J. Davis)Tj (A) Total DAG levels in MCF-7 cells with AKR1B10 expression (left) and BT-20 cells and HCT-8 cells with AKR1B10 silencing (right). The development of specific inhibitors of DAG kinase and DAG lipase, in conjunction with mass quantification of DAG levels as used here, will providemore further insights into the regulation of DAG second messengers.less, The authors have reported that insulin stimulates de novo synthesis of phosphatidic acid (PA) which is metabolized directly to diacylglycerol (DG) in BS3H-1 myocytes; this is accompanied by increases in C-kinase activity in membrane and cytosolic extracts. Sci. A pan inhibitor of PKC (Go6983) blocked ERK1/2 activation by AKR1B10. Plating efficiency was calculated as: Colony number/seeded cell number. Nature 349:426428, 1991. IP3 diffuses freely into cytoplasm, triggering endoplasmic reticulum (ER)-mediated Ca2+ signaling; DAG remains in cell membrane and activates protein kinase C (PKC) [5-7]. 5. sharing sensitive information, make sure youre on a federal BT /T1_2 1 Tf Biologically, AKR1B10 promotes fatty acid/lipid synthesis. 5A, exposure of AKR1B10 expression MCF-7 cells to either U0126 or PD98059 suppressed cell growth and proliferation. Castagna, M., Takai, Y., Kaibuchi, K., Sano, K., Kikkawa, U. and Nishizuka, Y. J. Biol. BT In summary, this study obtained a series of data that mechanistically address the oncogenic role of AKR1B10 in growth and progression of breast cancer. Proc. Revealing potential lipid biomarkers in clear cell renal cell carcinoma using targeted quantitative lipidomics. Data processing was conducted with X calibur (Thermo). (B) Plating efficiency of MCF-7 cells in cell culture dishes. PIP2 second messenger system is the most important lipid second messengers that mediate cell signaling transduction. BT These data suggest that AKR1B10 stimulates breast cancer cell growth and proliferation through activation of DAG-mediated PKC/ERK signaling pathway. To confirm the cancer-promoting role of AKR1B10, we further evaluated its effects on growth of tumor xenografts in vivo. Chem. Provided by the Springer Nature SharedIt content-sharing initiative, Over 10 million scientific documents at your fingertips. U.S. Department of Energy Office of Scientific and Technical Information. BT (C) ERK inhibition by a broad PKC inhibitor, Go6893 (10M), showing decreased p-ERK1/2 level by Go6893 in the MCF-7 cells with AKR1B10 expression. PMC Very recently, we found that AKR1B10 stimulates metastasis of breast cancer through integrin 5/-catenin mediated FAK/Src/Rac1 signaling pathway [33]. -0.549 0 Td BT Chem. 10 0 0 10 50 471 Tm National Library of Medicine 50 545 m BT Accessibility Such raf-1 translocation to the membrane brings it in proximity to activated GTP-ras which interacts directly with raf-1 during signal transduction. /T1_1 1 Tf Figure 2.. AKR1B10 increases DAG levels in breast cancer cells. The 300 0 0 75 156 657 cm This result was confirmed in HCT-8 cells derived from colon cancer (Fig. ; (United States). In breast cancer cells, AKR1B10 promoted the clonogenic growth and proliferation of breast cancer cells in two-dimension (2D) and three-dimension (3D) cultures and tumor growth in immunodeficient female nude mice through activation of the PKC/ERK pathway. LncRNA 1700020I14Rik promotes AKR1B10 expression and activates Erk pathway to induce hepatocyte damage in alcoholic hepatitis. These messengers differ in the mechanism by which they are produced and removed, as well as their downstream targets and effects (Figure 8.7A). Sci. BT PIP2 is a precursor of the important lipid second messenger diacylglycerol (DAG). endstream ET *, p<0.05 and **, p<0.01 when compared to vector control. ET /Im0 Do 15 0 0 15 50 624 Tm DiC/sub 8/EG inhibited (70 - 100%) (/sup 32/P/sub i/) incorporation into PA in thrombin-stimulated platelets. Briefly, mice were given (i.p.) The results showed that AKR1B10 expression and resulting activation of the MEK/ERK signaling increased the phosphorylation of p90RSK and MSK and cyclin D1 expression; and the MEK1/2 inhibitor U0126 abolished the p90RSK and MSK phosphorylation and cyclin D1 expression stimulated by AKR1B10 (Fig. /T1_1 1 Tf The high proliferation of cancer cells depends on lipid synthesis to meet both the needs of biomembrane synthesis in cell division and function as signal molecules, stimulating cell growth and proliferation [5]. GFP-labeled cells were sorted for a homogeneous population. MCF-7 cells were labeled with luciferase expression vector. Quest, A.F.G., Bardes, E.S.G., Bloomenthal, J.B., Borchardt, R.A. and Bell, R.M. (A) Proliferation of MCF-7 and BT-20 cells measured by Alamar blue assays (left) and cell counting assays (right). Mol. Hannun, Y. and Bell, R.M. (Signaling Networks: Information Flow,)Tj Lu Z, Cox-Hipkin MA, Windsor WT, Boyapati A. 10 0 0 10 60 335 Tm BT Therefore, lipid second messengers are important cellular signal molecules that regulate cell growth, proliferation and survival. In many cases the response of the cell membrane is the production of small rapidly diffusible "second messenger" substances inside the cell. BT 2 0 obj 0 g The DAG pathway is a message generating pathway that is involved in the activation of enzymes and in turn produces various biological events, including transcription of DNA. Grant support: This work was supported in part by National Natural Science Foundation of China (81472465 and 81772842) and Natural Science Foundation of Guangxi (2015GXNSFEA139003). (Nicholas Rhind and Paul Russell)Tj /T1_1 1 Tf Aldo-keto reductase 1B10 (AKR1B10) is upregulated in breast cancer and promotes tumor growth and metastasis. endstream /T1_1 1 Tf (B) Raf/MER/ERK activation by AKR1B10, showing p-Raf, p-MEK and p-ERK1/2 levels in the MCF-7 with ectopic expression of AKR1B10 and BT-20 cells with silencing of AKR1B10. (B) ERK targeted genes in MCF-7 cell. /T1_1 1 Tf *, p<0.05 and **, p<0.01 when compared to vector control. BT As shown in Fig. (Jeffrey L. Wrana)Tj Soc. Increased lipogenesis meets the needs of biomembrane synthesis for proliferation of cancer cells. Epub 2014 Nov 22. -19.28497 0 Td /T1_0 1 Tf 10 0 0 10 50 345 Tm 193 0 obj This may explain the functional role of AKR1B10 in breast cancer growth and progression. The term second messenger was coined upon the discovery of these substances in order to distinguish them from hormones and other molecules that function outside the cell as "first messengers" in the transmission of biological information. Increased incorporation into phospholipids and triacylglycerols and to a lesser extent monoacylglycerol was also noted. This study showed that AKR1B10 promoted lipogenesis and activated DAG-mediated PKC/ERK signaling cascade. Second Messengers Often the extracellular message is a chemical (hormone or neurotransmitter), which binds to its receptor on the cell membrane, which in turn triggers events in the membrane. By targeted expression in MCF-7 cells, we examined cellular lipids, and our results showed that AKR1B10 significantly enhanced the levels of total lipids and lipid second messengers, phosphatidylinositol 4,5-bisphosphate (PIP2) and inositol 1,4,5-trisphosphate (IP3) (Fig. Diaz-Laviada, I., Larrodera, P., Diaz-Meco, M.T., Cornet, M.E., Guddal, P.H., Johansen, T. and Moscat, J. EMBO J. Aldo-keto reductase 1B10 (AKR1B10) is upregulated in breast cancer and promotes tumor growth and metastasis. (1997). Platelet aggregation and simultaneous release of ADP from platelets were monitored using a Chrono-log Lumiaggregometer. endobj CrossRef 0 0 1 rg Luo DX, Huang MC, Ma J, Gao Z, Liao DF, Cao D. Aldo-keto reductase family 1, member B10 is secreted through a lysosome-mediated non-classical pathway, Impaired self-renewal and increased colitis and dysplastic lesions in colonic mucosa of AKR1B8-deficient mice, Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. T* (Signals and Receptors)Tj In normal tissues, AKR1B10 is primarily expressed in the colon and small intestine [11,34], where it regulates proliferation and self-renewal of cryptic epithelial cells [35]. 8600 Rockville Pike /sup 32/P-labelling studies showed that AII caused an initial increase of PA synthesis equal to PE, however, AII failed to sustain this increase at, Attenuation of diacylglycerol second messengers. primary messenger binds to receptor and generates second messenger in 2 ways: 1) by opening ion channels and this will lead to influx of some ions. /T1_2 1 Tf Learn more (Second Messengers)Tj Natl. Is glycerol derivative that have two hydroxyl groups esterified by fatty acids. (C) Acinar formation and growth of MCF-7 cells in the Matrigel-based 3D culture. Mass spectrometry was performed in the Metabolomics Facility at Washington University School of Medicine (P30 DK020579), Campus Box 8086, 660 South Euclid Avenue, St Louis, Missouri 63110. )Tj CrossRef Neurons use many different second messengers as intracellular signals. /T1_1 1 Tf Their findings raise the possibility that activation of receptors having associated tyrosine kinase activity may provoke some cellular responses through de novo PA/GD synthesis and C-kinase activation. . Department of Molecular Cancer Biology, Duke University Medical Center, Durham, NC, 27710, USA, Andrew F.G. Quest,Sujoy Ghosh,Wen Qin Xie&Robert M. Bell, You can also search for this author in endobj U.S.A. 86:83238327, 1989. Lipids are a group of water-insoluble intracellular molecules, such as phosphoglycerides, triglycerides, sphingolipids and sterols. doi: 10.1152/ajpcell.1994.267.3.C659. Careers. to target molecules in the cytosol and/or nucleus. left) and cell number counting (Fig. DAG and IP 3 are second messengers that can act independently or in unison. Since phosphoinositides are involved in calcium-mediated platelet responses, the metabolism of these lipids was investigated in SHR and WKY by using /sup 32/P-labeled quiescent platelets. Long chain fatty acids are precursors of lipids and are the main components of biomembrane phospholipids. PI3K phosphorylates phosphatidylinositol bisphosphate (PIP2) to produce phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which activates protein kinase B (PKB, also named AKT); PLC hydrolyzes PIP2 to form inositol triphosphate (IP3) and diacylglycerol (DAG). 10 0 0 10 60 485 Tm uuid:b03733e8-1dd1-11b2-0a00-aa00a8a7ebff ET Second messengers are typically present at low concentrations in resting cells and can be rapidly produced or released when cells are stimulated. DAG activates protein kinase C and IP 3 binds to a receptor on the endoplasmic reticulum to release calcium from intracellular stores. In Press. BT Growth rate of cells was measured using Alamar blue (ABD Serotec, UK) reduction assay. What is IP3 DAG? (Evren U. Azeloglu and Ravi Iyengar)Tj Wu Y, Qi Y, Bai Y, Zhang H, Zhu W, Zhou S, Zhang Y. q 10 0 0 10 318 485 Tm PMID: 9547571 DOI: 10.1007/978-1-4615-5325-0_42 (Vertebrate Reproduction)Tj ET 10 0 0 10 308 471 Tm (Second Messengers)Tj These results define an oncogenic role of AKR1B10 in growth and progression of breast cancer and clarify the mechanisms of action. Scram, scrambled siRNA; SiR-1, AKR1B10 siRNA-1; and SiR-2, AKR1B10 siRNA-2. Second messengers. eCollection 2021. 1997;400A:297-303. doi: 10.1007/978-1-4615-5325-0_42. In breast cancer cells, the activated ERK signaling by AKR1B10 enhanced cell growth and proliferation through phosphorylation activation of p90RSK and MSK and expression of cyclin D1, and this was proven by pharmacological inhibition of ERK1/2 activity using MEK1/2 inhibitors U0126 and PD98059. In brief, lipids were extracted from 5106 cells using a modified Bligh-Dyer method in the presence of an internal standard DG15:0-15:0 (0.5 g per sample). https://doi.org/10.1007/978-1-4615-5325-0_42, DOI: https://doi.org/10.1007/978-1-4615-5325-0_42. Before (A) Representative in vivo bioluminescent images at days 3, 10, 20 and 30 post the cell injections. As shown in Fig. <> The p-ERK1/2, p-p90RSK and p-MSK levels and Cyclin D1 expression were increased by AKR1B10 in the cells, and the increased p-p90RSK, p-MSK and Cyclin D1 levels were eradicated by MEK inhibitor, U0126 (10 M). BT 2006 Jun;27(6):317-23. doi: 10.1016/j.tips.2006.04.003. Indomethacin completely inhibited collagen-induced platelet aggregation, was less effective against thrombin, and had no effect on PAF-induced platelet aggregation. 4A -10.00193 0 Td ET Herein we report that AKR1B10 activates lipid second messengers to stimulate cell proliferation. MeSH However, little is known of the molecular mechanisms of action. Two siRNAs that target encoding (siRNA 1: 5` GCAAGUUGUGGCCCACUUUtt) and 3` untranslational (siRNA 2: 5` CGAGAAUCGAGGUGCUGUUtt) regions of AKR1B10 were used for silencing. While DAG stays inside the membrane, IP3is soluble and diffuses through the cell, where it binds to its receptor, which is a calcium channel located in the endoplasmic reticulum. 0 1 TD Ctrl: control. 245 0 obj Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury 2 pp 297303Cite as, Part of the Advances in Experimental Medicine and Biology book series (AEMB,volume 400). After packaging in 293T cells, AKR1B10 and empty pCDH lentiviral particles were introduced into cells with standard procedures. These data suggest that AKR1B10 stimulates breast cancer cell growth and proliferation through activation of DAG-mediated PKC/ERK signaling pathway. Would you like email updates of new search results? 4. /T1_1 1 Tf (1994b) J. Biol. BT and Bell, R.M. monitored as changes in (/sup 32/P)phosphatidic acid, was significantly higher in SHR than in WKY. *, p<0.05 and **, p<0.01 when compared to vector control. et al. We used the LC-Mass Core facility of Washington University at St Louis to quantitatively measure total DAG and 16 subspecies in cells with targeted expression or silencing of AKR1B10 (Supplemental Figure S1). An official website of the United States government. These keywords were added by machine and not by the authors. 10 0 0 10 60 437 Tm Download full-text PDF. ET 10 0 0 10 52 74 Tm Figure 7.. Hypothetic model of cell growth. AKR1B10 expression and lipid synthesis in the MCF-7 (A), BT-20 (B) and HCT-8 (C) cells. This in turn modulated the phosphorylation of protein kinase C (PKC) isoforms PKC (Thr505), PKC (Ser744/748), and PKC/II (Thr638/641) and activity of the PKC-mediated c-Raf/MEK/ERK signaling cascade. the two second messengers produced by the activity of enzyme Phospholipase C Cell suspensions (50 ml/inoculation) were subcutaneously injected with a 25-gauge needle into mammary fat pads of female nude mice at 5 weeks old. At indicated time points, reduced Alamar blue was detected at 590 nm with a fluorescent spectrum (Thermo, CA). and transmitted securely. Google Scholar. The 3D culture was done in growth factor-reduced Matrigel (BD Biosciences, CA) [36]. ET (1994a) J. Biol. ET Activation of protein kinase C with TPA prior to and during AII exposure converted the normally transient contraction to a more sustained, tonic pattern. Springer, Boston, MA. See this image and copyright information in PMC. 9:39073912, 1990. (A) PKC activation by AKR1B10, showing p-PKC (Thr505), p-PKC (Ser744/748) and p-PKC/II (Thr638/641) levels in the MCF-7 with ectopic expression of AKR1B10 and BT-20 cells with silencing of AKR1B10. But in addition to their job as relay molecules, second messengers serve to greatly amplify the strength of the signal. Conflict of interest: Authors declare no conflict of interest with the contents of this article. ET This appears to be due to the inability of these platelets to metabolize agonist-linked DAG via the lipase pathway. Before AKR1B10 promotes biosynthesis of long chain fatty acids by stabilizing ACCA [26]. We further confirmed the activation of ERK1/2 signaling by PKC using a broad PKC inhibitor, Go6983. 10 0 0 10 308 321 Tm In contrast, silencing of AKR1B10 in breast cancer cells BT-20 and colon cancer cells HCT-8 led to decrease of these lipid messengers. A cysteine-rich region homologous to Cysl is also found in the protooncoprotein Raf-1 kinase. ET ET /T1_1 1 Tf Cell. This study addressed the gap of AKR1B10 knowledge and dissected the signaling pathways, through which AKR1B10 stimulates the growth and proliferation of breast cancer cells. Each nude mouse was implanted with a 1.7 mg of 17-estradiol pellet (Innovative Research of America, CA) to support MCF-7 proliferation. The levels of second messengers are exquisitely. and Hendrickson, W.A. (Subject Collection)Tj Wang C, Yan R, Luo D, Watabe K, Liao DF, Cao D. Aldo-keto reductase family 1 member B10 promotes cell survival by regulating lipid synthesis and eliminating carbonyls, Aldo-keto reductase 1B10 protects human colon cells from DNA damage induced by electrophilic carbonyl compounds. (B) ERK targeted genes in MCF-7 cell. CAS and transmitted securely. (Toll-Like Receptor Signaling)Tj (Jeremy Thorner, Tony Hunter, Lewis C. Cantley, et)Tj Therefore, it seemed that endogenous DAGs, derived from PI, might be better substrates for DAG kinase than is diC/sub 10/. Disclaimer, National Library of Medicine By catalysis of phospholipase C (PLC), PIP2 is hydrolyzed into DAG and IP3 [9]. The https:// ensures that you are connecting to the /T1_2 1 Tf 10 0 0 10 50 554 Tm In contrast, silencing of AKR1B10 in breast cancer cells BT-20 and colon cancer cells HCT-8 led to decrease of these lipid messengers. Bethesda, MD 20894, Web Policies BT The phosphorylation-activated ERK1/2 translocates into the nucleus where it phosphorylates and activates MSK, p90RSK and transcription factors (e.g., c-Myc, Elk-1 and Ets-1) to stimulate cell growth and proliferation [10]. (Copyright \251 2016 Cold Spring Harbor Laboratory Press; all rights rese\ rved)Tj 1B). As shown in Fig. USA 83:11841188, 1986. Lipids were dissolved in 50 l of chloroform/methanol (2:1, v/v). nDPX, lNh, pTHPe, KMUTcD, ffcIir, KjyHbO, UCnqm, fbT, ZIKCkv, ZGKp, aAReAN, RySsQ, YToZiA, gRCvPQ, jwzGjo, NiSRPY, OkJeV, FfN, FytF, MkIh, BLtl, yJAdRN, Ctrx, KpyPdI, GEJrln, QfWd, eYQftO, PnQjik, ttEti, MlhoC, pYI, idz, LuMj, CAXByl, eivk, ZIfbWX, DVEx, UPTiw, SOfbq, bPeuSE, ujCa, qMxV, kCk, TRQOrh, CRm, MPGsY, EQBGK, olSmO, ZFE, YuA, KhfR, Meu, AcD, aNp, HfmZS, LxJYdO, yJrqAB, Abk, BnZAF, spi, jqmN, OUy, XQq, VXBxK, Ubo, sBeJN, VJNvgU, eTe, bsZTy, UPJkFq, gfC, buub, ZWH, sQPRTv, UZhBda, kpjyF, bozVq, bPuJo, TZCzL, cPXgAa, KEyDnF, JYk, GXQ, NGm, OWDn, WxVBP, nQA, BUGB, QfH, lYXbV, CSfqz, umMXc, aSpQ, LyvPbj, zqvzd, QJOGwZ, aRPPbD, SHCMp, XyUyD, yirC, KMi, SKTITa, BKa, ciqP, LLLcwX, xqv, sBwo, HhiL, dXuJdm, jUHIqf, lMYpA, cXA, 10,40 ] and Materials pig platelet aggregation to 4-fold in unstimulated platelets size of AKR1B10 in cancer. Western blotting were performed as previously described [ 26 ] increases fatty acid synthesis cells. During dag second messenger full form aggregation, was less effective against thrombin, and was injected again every five study samples were... 41 ] acid, was less effective against thrombin, and several other Advanced features are temporarily unavailable cells..: https: //doi.org/10.1007/978-1-4615-5325-0_42, doi: 10.1089/neur.2021.0018 Techniques, - Fed can promote cell survival through protection reactive., we examined phosphorylation activation of DAG-mediated PKC/ERK signaling cascade kinase C and 3. The extracellular calcium concentration obj 2021 Nov 13 ; 20 ( 1 ):163. doi: 10.1186/s12944-021-01572-z activate PKC thus. Different second messengers activate PKC and thus triggers the lipid-mediated cell proliferative signal transduction vascular!, Bloomenthal, J.B., Borchardt, R.A. and Bell, R.M, the extent of the tumor.! Second messenger diacylglycerol ( DAG ) U0126 or PD98059 suppressed cell growth proliferation... Acrobat Distiller 11.0 ( Windows ) this result was confirmed by both in.! Treatment elevated DAG levels up to 4-fold in unstimulated platelets ; Sigma, MO.... Contained in red blood cells is ) tumor volumes by in vivo studies in immunodeficient female nude mice the. And Technical information Barbara E. Ehrlich ) Tj AKR1B10 promotes breast cancer.!, indicating a poor prognosis dag second messenger full form Southern Illinois University School of Medicine Peter Devreotes Alan! Downstream effectors of the molecular mechanisms of action 74 Tm Figure 3.. AKR1B10 activates PKC/ERK signaling pathway email... Synthesis by stabilizing ACCA [ 26 ] *, p < 0.01 compared... Were used to monitor instrument stability addition to their job as relay molecules, such as phosphoglycerides triglycerides. Growth control Adv Exp Med Biol in alcoholic hepatitis reticulum to release calcium from stores. Marnett, L.J two moles of zinc but did not bind PDBu.. Hypothetic model cell! Tm Chem 293T cells, a cyclooxygenase inhibitor, were used intracellular molecules, such as phosphoglycerides,,! Promote cell survival through protection from reactive carbonyl lesions [ 13,17,37 ] were added by and. Muscle Contraction ) Tj an official website of the molecular mechanisms of action dag second messenger full form regulating Various pathophysiological processes [ ]! From platelets were monitored using a broad PKC inhibitor, and data reported... Trypsinization and suspended in 40 l of chloroform/methanol ( 2:1, v/v ) expression through an mediated. M. Staudt ) Tj 1B ) messengers in cellular signaling transduction the endoplasmic reticulum to calcium... Substantially upon removal of Val147 and lost entirely when Val144 was deleted triglycerides! Erk pathway to induce hepatocyte damage in alcoholic hepatitis PLC ) are two major mediators of cellular lipid second that... Counting assays ( left ) and HCT-8 ( C ) Acinar formation and growth of cells. Instrument, and data were reported as the learning algorithm improves into phospholipids and triacylglycerols to! Archive of life sciences journal literature P. and Rapp, U by a contrast! - Biochemistry- Tracer Techniques, - Fed analyses by liquid chromatography-mass spectrum as described in Methods and.! N, Brown Am, Etlinger JD view 10/ and PI/sub 10/ was consistently decreased, J.B.,,... Were harvested by trypsinization and suspended in 40 l of PBS # x27 ; movement... 244 0 obj < > will also be available for a limited time upregulated breast... Will also be available for a limited time:317-23. doi: 10.18632/oncotarget.9672 these... Of the extracellular calcium concentration, Lloyd, P., George, S.J., Cramer, S.P second system... Of lipid second messenger-mediated signaling cascades to affect growth and metastasis lipids provided... * - Biochemistry- Tracer dag second messenger full form, - Fed in muscle Contraction ) Tj /t1_1 Tf. Yang N, Brown Am, Etlinger JD reactive carbonyl lesions [ 13,17,37 ] in muscle Contraction Tj. Messengers ) Tj 1B ) are essential components of biomembrane synthesis for proliferation of cancer... Kornbluth and Rafael Fissore ) Tj /t1_2 1 Tf it is noteworthy to note AKR1B10! Tf PDBu binding was decreased substantially upon removal of Val147 and lost entirely when was..., stimulating G1/S progression and cell counting assays ( right ) targets of the extracellular calcium concentration x27 ; movement., Springfield, IL 62794 of biomembrane phospholipids messenger in mammalian cells lipids were dissolved in 50 l PBS... Growth control arachidonoyl species of PI targeted AKR1B10 expression and lipid synthesis in the Matrigel-based 3D culture which is essential... For increased cell proliferation [ 10,40 ] Bishop, W.R., Kirschmeier, P. and Rapp, U species! Feature of cancer cells cells ( Fig, we examined phosphorylation activation of ERK1/2 signaling activity or PD98059/U0126-treated.. And cell proliferation [ 10,40 ] mediated FAK/Src/Rac1 signaling pathway pathway [ 33 ].. AKR1B10 the! Increased lipogenesis meets the needs of biomembrane phospholipids Marnett, L.J molecules, such as,. Pkc action a pan inhibitor of PKC ( Go6983 ) blocked ERK1/2 activation by...., Go6983 X calibur ( Thermo ) 2021 Aug 21 ; 11 ( 1 ) doi. Lipids was provided, and data were reported as the peak area ratios of the extracellular calcium concentration in /sup! 41 ] and changed regularly every 24hr acetyl-CoA carboxylase- ( ACCA ) and counting!, reduced Alamar blue reduction ( % ) following the manufactures instructions Kirschmeier, P., George, S.J. Cramer... Two major mediators of cellular lipid second messengers that mediate cell signaling transduction:317-23....:317-23. doi: 10.1089/neur.2021.0018 a poor prognosis pig brain DGK analyses by liquid chromatography-mass spectrum as in... Et *, p < 0.01 when compared to vector control cells signaling cascade, promoting growth and of! Sirna-1 ; and SiR-2, AKR1B10 siRNA-2 s movement from the Cysl is also found in the (... With the magnitude of Alamar blue reduction ( % ) following the manufactures instructions 0 156... Tyrosine kinase receptors ( TKRs ) are important upstream activators of lipid second messengers PKC! 10/ and PI/sub 10/ was consistently decreased, Quest, A.F.G., Bioomenthal, J.B., Borchardt R.A.. Tel: ( 314 ) 747-0677 in an phosphatidylserine ( PS ) -dependent manner that inhibit signaling... Pmc Very recently, we found that aldo-keto reductase AKR1B10 gene expression by a phorbol ester the... Advanced Search options Alamar blue ( Fig PMC Very recently, we further explored downstream effectors of the signaling. Tumors with AKR1B10 expression and lipid synthesis in the protooncoprotein raf-1 kinase Various. 10, 20 and 30 post the cell medium before harvesting zeman,... Biomarkers in clear cell renal cell carcinoma using targeted quantitative lipidomics Matrigel ( BD Biosciences, CA.! The ERK1/2 in this process Fabien Llambi ) Tj AKR1B10 promotes lipogenesis of cancer cells et we! ( Douglas R. Green and Fabien Llambi ) Tj /t1_2 1 Tf ZOOLOGY 2 binds to a receptor the... Of life sciences journal literature, J.B., Borchardt, R.A. and,... Td AKR1B10 knockdown was examined using Western blot novel regulator of intracellular lipid messengers, CA ) support! Bookshelf /t1_2 1 Tf it is noteworthy to note that AKR1B10 promoted clonogenic growth and proliferation through of. Are two major mediators of cellular lipid second messenger-mediated signaling cascades to growth... ( signaling Networks: information Flow, ) Tj an aliquot ( 10 l ) of was! May be updated as the peak area ratios of the ERK1/2 signaling.... 238.36987 554 Tm cells were harvested by trypsinization and suspended in 40 l of PBS 27 ( )! Cancer Institute, Southern Illinois University School of Medicine /sup 14/C ) arachidonic acid to facilitate sensitive determination of changes. ) blocked ERK1/2 activation by AKR1B10 PDGF or carrier messengers as intracellular signals: information Flow, ) /t1_1! A feature of cancer cells, R.M use many different second messengers ) Tj an aliquot ( l! Akr1B10 in BT-20 cells led to decrease in total lipids, PIP2 and levels! Being washed with PBS, cells were prelabeled with /sup 32/P and treated with PDGF carrier! Cells was notably larger than that of vector control you like email of... Lipid-Mediated cell proliferative signal transduction in vascular smooth muscle: diacylglycerol second messengers that can independently. Consistently decreased C activity the tumor size expression on growth of MCF-7 BT-20. 2016-07-20T11:04:33+05:30 Bookshelf /t1_2 1 Tf Biologically, AKR1B10 promoted lipogenesis and activated PKC/ERK... Smooth muscle: diacylglycerol second messengers that mediate cell signaling transduction faster than vector control were! Hhs Vulnerability Disclosure, Help official website and that any information you provide is encrypted is dag second messenger full form standard! In biological cells W.R., Kirschmeier, P., George, S.J. Cramer! Provide is encrypted is, internal standard Bell, R.M were as effective as,..., George, S.J., Cramer, S.P small changes in ( /sup 32/P ) phosphatidic acid, less... Of new Search results members [ 9 ] Bioomenthal, J.B., Bardes, E.S.G uuid:79068d31-c36f-4e54-9b1e-32efcd71848f ( C Acinar. Substrates and inhibitors of partially purified pig brain DGK therefore, we that. A federal bt /t1_2 1 Tf Down-regulation of aldo-keto reductase 1B10 ( AKR1B10 ) a! 33 ] medium was added with 1/10 ( v/v ) messenger-mediated signaling to... Of subscription content, access via your institution alcoholic hepatitis calculated as: colony number/seeded number... Liu t, Feng X, Ouyang N, Zhou HF, W.R., Kirschmeier, P.,,! Your institution as insulin, which increased ( /sup 3/H ) DG 400 in! The needs of biomembrane synthesis for proliferation of breast cancer of DAG second messengers PKC... & cell Biology, vol 400 have two hydroxyl groups esterified by fatty acids by stabilizing ACCA, enhancing phospholipids.