/T1_2 1 Tf 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). Only the lipid species with CV < 15% in QC sample were reported. (Cell Signaling and Stress Responses)Tj Ahmed, S., Kozma, R., Lee, J., Monfries, C., Harden, N. and Louis, L. Biochem. Oncotarget. and Bell, R.M. PKC is an important oncogenic kinase that activates ERK1/2 signaling to promote cancer growth and progression [8,9]. At indicated time points, cells were trypsinized, stained with trypan blue and counted by a Vi-cell counter (Beckman coulter, CA). (Post-Genomic Era)Tj Smith, M.R., DeGudicibus, S.J. Interestingly, this study found that aldo-keto reductase 1B10 is a novel regulator of intracellular lipid messengers. Following thrombin stimulation, (/sup 32/P)phosphatidic acid formation likely reflects the initial agonist-receptor interaction; therefore, these results suggest that phospholipase C activity is enhanced in platelets of SHR and that the hypersensitivity of phospholipase C in SHR may play a role in the overall alteration of cell calcium handling and, hence, in the platelet responses of SHR. Figure 2.. AKR1B10 increases DAG levels in breast cancer cells. 0 g 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. Kolch, W., Heidecker, G., Lloyd, P. and Rapp, U. 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). 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. It was observed that cyclooxygenase products were responsible for collagen-induced guinea pig platelet aggregation. (Vertebrate Reproduction)Tj 226 0 obj 10 0 0 10 318 461 Tm PKC isoforms are master kinases of the important signaling cascade, Raf/MEK/ERK, regulating a variety of cellular events, such as cell survival and proliferation. BT (C) Acinar formation and growth of MCF-7 cells in the Matrigel-based 3D culture. DAG has a great role in biochemical signaling. BT AKR1B10 knockdown was examined using Western blot. BT /T1_2 1 Tf (Subversion of Cell Signaling by Pathogens)Tj 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. DAG activates protein kinase C and IP 3 binds to a receptor on the endoplasmic reticulum to release calcium from intracellular stores. ET 2 0 obj /T1_0 1 Tf 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]. Figure 3.. AKR1B10 activates PKC/ERK signaling pathway in breast cancer cells. /T1_3 1 Tf /T1_1 1 Tf FOIA Diaz-Laviada, I., Larrodera, P., Diaz-Meco, M.T., Cornet, M.E., Guddal, P.H., Johansen, T. and Moscat, J. EMBO J. **, p<0.01 when compared to the vector control or PD98059/U0126-treated cells. (1994) The Regulatory domain of protein kinase C gamma: studies of phorbol ester binding to individual and combined functional segments expressed as GST-fusion proteins indicate a complex mechanism of regulation by phospholipids, phorbol esters and divalent cations (Submitted), Ghosh, S., Xie, W.Q., Quest, A.F.G., Malbrouk, G.M., Strum, J.C. and Bell, R.M. 2022-12-11T18:18:39-08:00 2) by activation of enzyme in cell membrane. /T1_0 1 Tf /T1_1 1 Tf Second messengers. 266:1833018338, 1991. <>stream /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. /Im0 Do What is IP3 DAG? the two second messengers produced by the activity of enzyme Phospholipase C <>/ProcSet[/PDF/Text/ImageC]/XObject<>>>/Type/Page>> 2017 May 16;8(20):33694-33703. doi: 10.18632/oncotarget.16624. (Jeffrey L. Wrana)Tj Aldo-keto reductase 1B10 (AKR1B10) is upregulated in breast cancer and promotes tumor growth and metastasis. ET second messenger, molecule inside cells that acts to transmit signals from a receptor to a target. government site. 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]. More impressively, AKR1B10 promoted clonogenic growth of MCF-7 cells, a feature of cancer cells. ET 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. These data suggest that AKR1B10 stimulates breast cancer cell growth and proliferation through activation of DAG-mediated PKC/ERK signaling pathway. Oppositely, silencing of AKR1B10 in BT-20 cells led to decrease in total lipids, PIP2 and IP3 (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. Figure 7.. Hypothetic model of cell growth. -0.549 0 Td PMC legacy view 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. CrossRef /T1_0 1 Tf 0 g Two siRNAs that target encoding (siRNA 1: 5` GCAAGUUGUGGCCCACUUUtt) and 3` untranslational (siRNA 2: 5` CGAGAAUCGAGGUGCUGUUtt) regions of AKR1B10 were used for silencing. 10 0 0 10 308 447 Tm 189 0 obj Protein lysates, SDS-PAGE and Western blotting were performed as previously described [26]. endobj U.S.A. 86:83238327, 1989. BT <> Increased PIP2 and IP3 levels in breast cancer cells encouraged an extended study on DAG and the DAG-mediated signaling transduction. 50 545 m Tumor volume was monitored by both in vivo imaging and caliper measurements. BT /T1_2 1 Tf endobj 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). DiC/sub 10/ was added to the cell medium before harvesting. A scrambled siRNA with random RNA sequences was used as a control. (A) Representative in vivo bioluminescent images at days 3, 10, 20 and 30 post the cell injections. Chem. 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. (Second Messengers)Tj further insights into the regulation of DAG second messengers. 0 1.00001 TD (Signaling in Muscle Contraction)Tj AKR1B10 is a novel oncogenic protein in breast cancer. and Bell, R.M. Lipid samples and standards were visualized by coloration in staining solution (0.12 M NaCl, 20% methanol, and 300 mg/liter Coomassie Blue). Various in vitro assays for enzymes involved in arachidonic acid release and metabolism were conducted. (B) Tumor volumes by in vivo bioluminescence at photon/second. endobj 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]. (Signaling by the TGF)Tj ET 11 0 0 11 205.27596 579.99988 Tm et al. 121 0 obj https://doi.org/10.1007/978-1-4615-5325-0_42, DOI: https://doi.org/10.1007/978-1-4615-5325-0_42. Plating efficiency was calculated as: Colony number/seeded cell number. It is noteworthy to note that AKR1B10 can promote cell survival through protection from reactive carbonyl lesions [13,17,37]. (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. 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. ET (Nicholas Rhind and Paul Russell)Tj Meth. DAG second messengers: molecular switches and growth control Adv Exp Med Biol. BT BT J. Biol. Wu Y, Qi Y, Bai Y, Zhang H, Zhu W, Zhou S, Zhang Y. In contrast, silencing of AKR1B10 in breast cancer cells BT-20 and colon cancer cells HCT-8 led to decrease of these lipid messengers. At indicated time points, reduced Alamar blue was detected at 590 nm with a fluorescent spectrum (Thermo, CA). Chem. (http://cshperspectives.cshlp.org/cgi/collection/ )Tj 10 0 0 10 318 403 Tm DAG and subspecies were measured quantitatively by liquid chromatography-mass spectrum as described in Methods and Materials. BY, DAMARIS BENNY DANIEL I Msc. Part of Springer Nature. /T1_1 1 Tf BT Acini were photographed by a phase contrast microscopy (Carl Zeiss, CA). 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. (A) Proliferation of MCF-7 and BT-20 cells measured by Alamar blue assays (left) and cell counting assays (right). PKD at the crossroads of DAG and PKC signaling. <> (B) Levels of various subspecies of DAG in MCF-7 (upper), BT-20 (lower left) and HCT-8 (lower right) cells. 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. DAG and IP 3 are second messengers that can act independently or in unison. Herein we report that AKR1B10 activates lipid second messengers to stimulate cell proliferation. Natl. /T1_2 1 Tf -8.83699 0 Td More importantly, AKR1B10 is a mediator of long chain fatty acid synthesis. Springer, Boston, MA. /T1_2 1 Tf 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. Proc. 0 1 TD (Mary B. Kennedy)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. Figure 1.. AKR1B10 promotes lipogenesis of cancer cells. Cells were prelabeled with /sup 32/P and treated with PDGF or carrier. (B) ERK targeted genes in MCF-7 cell. Lipids were dissolved in 50 l of chloroform/methanol (2:1, v/v). Qualitative analyses by liquid chromatography-mass spectrum (LC-MS) revealed that AKR1B10 regulated the cellular levels of total DAG and majority of subspecies. Phospholipid, sphingolipids and sterols are important building blocks of biological membranes. 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. PubMed However, little is known of the molecular mechanisms of action. -14.28398 0 Td 10 0 0 10 318 358.99997 Tm (A) Total DAG levels in MCF-7 cells with AKR1B10 expression (left) and BT-20 cells and HCT-8 cells with AKR1B10 silencing (right). These results define an oncogenic role of AKR1B10 in growth and progression of breast cancer and clarify the mechanisms of action. 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. 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). [251 0 R 252 0 R 253 0 R 254 0 R] (B) ERK targeted genes in MCF-7 cell. Download preview PDF. The gap of knowledge of AKR1B10 is how the AKR1B10-induced lipogenesis leads to growth and metastasis of breast cancer. Phospholipids are essential components of bio-membranes and important second messengers in cellular signaling transduction, regulating various pathophysiological processes [1-3]. Similar to other. Right panel: Quantitative analyses of indicated proteins. (http://cshperspectives.cshlp.org/)Tj Proc. These compounds were tested in human platelets. 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). (C) Acinar formation and growth of MCF-7 cells in the Matrigel-based 3D culture. /T1_2 1 Tf 1Department of Medical Microbiology, Immunology & Cell Biology, Simmons Cancer Institute, Southern Illinois University School of Medicine. (Alexandra C. Newton, Martin D. Bootman and John)Tj Second messengers are typically present at low concentrations in resting cells and can be rapidly produced or released when cells are stimulated. /T1_0 1 Tf Diacylglycerol (DAG) and subspecies were quantitatively and qualitatively detected by LC-MS through Washington University Mass Spec Facility. BT ET CAS (Signaling Networks that Regulate Cell Migration)Tj 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. (1994) J. Biol. Therefore, AKR1B10-induced lipogenesis may have critical impact in cancer development and progression. Left panel: Quantitative analysis of band intensity. Keywords: Conflict of interest: Authors declare no conflict of interest with the contents of this article. After packaging in 293T cells, AKR1B10 and empty pCDH lentiviral particles were introduced into cells with standard procedures. 266:32153221, 1991. 267:1019310197, 1992. CAS Careers. 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. IP3: (n-s-tl), IP3 An intracellular second messenger molecule that stimulates the endoplasmic reticulum of the cell to release calcium. -8.11398 0 Td /T1_1 1 Tf 10 0 0 10 50 423 Tm (A) Inhibition of MCF-7 cell proliferation by MEK inhibitors, PD98059 and U0126 at 10 M or 20 M. AKR1B10 expression and lipid synthesis in the, Figure 2.. AKR1B10 increases DAG levels in. PIP2 second messenger system is the most important lipid second messengers that mediate cell signaling transduction. (Signals and Receptors)Tj ET This study showed that AKR1B10 promoted lipogenesis and activated DAG-mediated PKC/ERK signaling cascade. 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. AKR1B10; PKC/ERK cascade; breast cancer; diacylglycerol; lipid second messengers; phosphatidylinositol bisphosphate. Total lipids were extracted as described [15,38]. Lipid extracts and appropriate lipid standards (Sigma, MO) were spotted on silica gel (60; Sigma, MO). 5B). Unable to load your collection due to an error, Unable to load your delegates due to an error. 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. 562 568 l 194 0 obj Figure 3.. AKR1B10 activates PKC/ERK signaling pathway. An official website of the United States government. Arbortext Advanced Print Publisher 9.1.520/W ET Acad. 249 0 obj 4B). and PAF increased phospholipase C activity. S Figure 7.. Hypothetic model of cell growth and proliferation promoted by AKR1B10. Li W, Wang X, Zhang X, Gong P, Ding D, Wang N, Wang Z. Lipids Health Dis. ET 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). and Bell, R.M. <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/Properties<>>>/Rotate 0/Type/Page>> Together these data suggest that AKR1B10 promotes clonogenic growth and proliferation of breast cancer cells. (Protein Regulation in Signal Transduction)Tj J. Biol. More importantly, membrane phospholipids are a major group of lipid second messengers, mediating cellular signaling pathways of cancer cell growth and proliferation [1]. 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). The minimal sequence required for PDBu binding was elucidated by deletion analysis. This appears to be due to the inability of these platelets to metabolize agonist-linked DAG via the lipase pathway. /T1_1 1 Tf DAG activates important oncogenic signaling molecule PKC, and IP3 provokes ER-mediated calcium signaling, further activating PKC. 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. 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. The glycerol is linked with the fatty acid chain through ester linkages. PMC For cell number counting, cells (0.1106) were plated in 6-well plate. The NH2-terminal conserved histidine H102 was essential for both coordination of 1 zinc atom and PDBu binding. (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. /T1_2 1 Tf The levels of second messengers are exquisitely. (A) Mechanisms responsible for producing and removing second . But in addition to their job as relay molecules, second messengers serve to greatly amplify the strength of the signal. 2022 Feb 24;12:727505. doi: 10.3389/fonc.2022.727505. sharing sensitive information, make sure youre on a federal <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/Properties<>>>/Rotate 0/Type/Page>> Chem 261:93419347, 1986. /T1_0 1 Tf As shown in Fig. AKR1B10 expression and lipid synthesis in the MCF-7 (A), BT-20 (B) and HCT-8 (C) 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. (Doreen Cantrell)Tj BT right) assays. BT and Bell, R.M. *, p<0.05 and **, p<0.01 when compared to vector control. 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. T* The p90RSK, MSK and cyclin D1 functions as downstream targets of the ERK1/2 in this process. )Tj Zu X, Yan R, Robbins S, Krishack PA, Liao DF, Cao D. Reduced 293T cell susceptibility to acrolein due to aldose reductase-like-1 protein expression, Toxicological sciences : an official journal of the Society of Toxicology, Oxidative Stress and Carbonyl Lesions in Ulcerative Colitis and Associated Colorectal Cancer, Oxidative medicine and cellular longevity, Development of a 32P-postlabelling method for the detection of 1,N2-propanodeoxyguanosine adducts of crotonaldehyde in vivo, Microbially produced acetaldehyde from ethanol may increase the risk of colon cancer via folate deficiency, International journal of cancer Journal international du cancer, Structural basis for the high all-trans-retinaldehyde reductase activity of the tumor marker AKR1B10, Proceedings of the National Academy of Sciences of the United States of America, Aldo-keto reductases from the AKR1B subfamily: retinoid specificity and control of cellular retinoic acid levels, AKR1B10 induces cell resistance to daunorubicin and idarubicin by reducing C13 ketonic group. Chem. The pathway begins with the binding of extracellular primary messengers such as epinephrine, acetylcholine, and hormones AGT, GnRH, GHRH, oxytocin, and TRH, to their respective receptors. *, p<0.05 and **, p<0.01 when compared to vector control. (Downloaded from )Tj and Bell, R.M. This may explain the functional role of AKR1B10 in breast cancer growth and progression. ERK1/2 can phosphorylate T369 and T573 residues of p90RSK to enhance cell survival signals [10,39]. Would you like email updates of new search results? 1C). -1 TL /Im1 Do BT 50 96 m 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. 3A, AKR1B10 expression in MCF-7 cells enhanced the level of phosphorylated PKC (Thr505), PKC (Ser744/748) and PKC/II (Thr638/641). Y axis is in log10. (A) Inhibition of MCF-7 cell proliferation by MEK inhibitors, PD98059 and U0126 at 10 M or 20 M. 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. LncRNA 1700020I14Rik promotes AKR1B10 expression and activates Erk pathway to induce hepatocyte damage in alcoholic hepatitis. Q PubMed 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. and Hendrickson, W.A. 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 However, little is known of the molecular mechanisms of action. 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. doi: 10.1152/ajpcell.1994.267.3.C659. BT USA 83:11841188, 1986. 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. 10 0 0 10 60 437 Tm Such raf-1 translocation to the membrane brings it in proximity to activated GTP-ras which interacts directly with raf-1 during signal transduction. (2016; doi: 10.1101/cshperspect.a005926)Tj <> (Carl-Henrik Heldin, Benson Lu, Ron Evans, et al. 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. MeSH 2022-12-11T18:18:39-08:00 10 0 0 10 308 321 Tm 10 0 0 10 318 485 Tm Cell Death Discov. BT and Bell, R.M. PMID: 9547571 DOI: 10.1007/978-1-4615-5325-0_42 ( on December 11, 2022 - Published by Cold Spring Harbor Laboratory Press\ )Tj (Signal Transduction: From the Atomic Age to the)Tj Biol. 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]. 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. Revealing potential lipid biomarkers in clear cell renal cell carcinoma using targeted quantitative lipidomics. . 913 N. Rutledge Street, Springfield, IL 62794. Accessibility 10 0 0 10 318 311 Tm The beta isozymes of PLC are regulated by G-proteins (G-alphaq/11 and G-betagamma) Berridge (1989), Gilman (1989). endobj Signal transduction in vascular smooth muscle: diacylglycerol second messengers and PKC action. 8:138153, 1993. 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. Down-regulation of aldo-keto reductase AKR1B10 gene expression by a phorbol ester via the ERK/c-Jun signaling pathway. application/pdf Advances in Experimental Medicine and Biology, vol 400. (Signaling in Lymphocyte Activation)Tj Cell. Increased incorporation into phospholipids and triacylglycerols and to a lesser extent monoacylglycerol was also noted. Values were normalized for protein contents (CPM/mg of protein). ET 8600 Rockville Pike ET ET Lu Z, Cox-Hipkin MA, Windsor WT, Boyapati A. 10 0 0 10 50 345 Tm (In Press), Quest, A.F.G., Bardes, E.S.G. S Chem. House, C. and Kemp, B.E. The site is secure. Bookshelf The mechanism of enhanced phosphorylation of DAG was studied with dicaprylin (diC/sub 10/) as a probe. Exton, J.H. 2022 Springer Nature Switzerland AG. 10 0 0 10 50 471 Tm Analytical data of DAG subspecies demonstrated that targeted expression of AKR1B10 markedly increased the levels of majority of 16 DAG subspecies, but AKR1B10 silencing led to decrease of DAG subspecies (Fig. (G\366khan S. Hotamisligil and Roger J. Davis)Tj This result was confirmed in HCT-8 cells derived from colon cancer (Fig. 10 0 0 10 318 508.99997 Tm /T1_2 1 Tf 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. 10 0 0 10 308 495 Tm 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. Casey, P., Solski, P.A., Der, C.J. Very recently, we found that AKR1B10 stimulates metastasis of breast cancer through integrin 5/-catenin mediated FAK/Src/Rac1 signaling pathway [33]. Unable to display preview. ; (United States). A pan inhibitor of PKC (Go6983) blocked ERK1/2 activation by AKR1B10. J. AII (5 x 10/sup -7/M) causes only a transient contractile response, while PE (10/sup -5/M) causes a sustained tonic contraction. endstream Each nude mouse was implanted with a 1.7 mg of 17-estradiol pellet (Innovative Research of America, CA) to support MCF-7 proliferation. (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. 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. 2021 Aug 21;11(1):163. doi: 10.1186/s13578-021-00677-3. MOG treatment elevated DAG levels up to 4-fold in unstimulated platelets. 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 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. *, p<0.05 and **, p<0.01 when compared to vector control. In fact, AKR1B10 is upregulated in multiple solid cancers, such as liver, breast, lung and pancreatic cancers, being a potential prognostic biomarker [29-32]. uuid:b03733e8-1dd1-11b2-0a00-aa00a8a7ebff 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. /T1_1 1 Tf 1A). Am J Physiol. Indomethacin completely inhibited collagen-induced platelet aggregation, was less effective against thrombin, and had no effect on PAF-induced platelet aggregation. ET ET Acad. Feig, L.A. and Cooper, G.M. The rest of author panel assisted in animal welfare, experimental preparation, literature search, and data analysis or provided advices in the project design. All were found to be effective in stimulating glucose transport. Therefore, lipid second messengers are important cellular signal molecules that regulate cell growth, proliferation and survival. endobj ET 130 0 obj Lipid fractions were re-suspended into 50% methanol solution, and radioactivity were measured by scintillation counter (Beckman Instruments). Correlation analyses were conducted using Spearman correlation and multivariate canonical correlation. The p90RSK, MSK and cyclin D1 functions as downstream targets of the ERK1/2 in this process. 10 0 0 10 308 529 Tm AKR1B10 promotes breast cancer cell proliferation and migration via the PI3K/AKT/NF-B signaling pathway. In contrast, silencing of AKR1B10 in breast cancer cells BT-20 and colon cancer cells HCT-8 led to decrease of these lipid messengers. (eds) Eicosanoids and Other Bioactive Lipids in Cancer, Inflammation, and Radiation Injury 2. )Tj Sun Y, Liu WZ, Liu T, Feng X, Yang N, Zhou HF. 0 0 1 rg total glycerolipids, although none were as effective as insulin, which increased (/sup 3/H)DG 400% in 1 minute. 4A, ectopic expression of AKR1B10 in MCF-7 increased the cell growth and proliferation compared to the empty vector control, whereas silencing of AKR1B10 in BT-20 cells decreased the cell proliferation. (\240)Tj A number of DAG analogs were tested as substrates and inhibitors of partially purified pig brain DGK. 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. IS, internal standard. A.C. Newton et al. <> The 2018 Oct; 57(10): 13001310. Mol. ET A cysteine-rich region homologous to Cysl is also found in the protooncoprotein Raf-1 kinase. Introduction Diacylglycerol (DAG) is a lipid signal messenger which is an essential second messenger in mammalian cells. Platelets were labeled with (/sup 14/C)arachidonic acid to facilitate sensitive determination of small changes in platelet phospholipids during platelet aggregation. Figure 4.. AKR1B10 promotes growth and proliferation. Diacylglycerol(DAG) derived from phosphatidylinositol activates protein kinase C in agonist-stimulated cells. U0126 and PD98059 are MEK1/2 inhibitors that inhibit ERK1/2 signaling activity. 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. ET ET BT (For additional articles in this collection, see )Tj AKR1B10 is an oncoprotein that promotes growth and progression of breast cancer. official website and that any information you provide is encrypted ET G-protein coupled receptors (GPCRs) and tyrosine kinase receptors (TKRs) are important upstream activators of lipid second messengers. ET /T1_1 1 Tf 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. Therefore, it seemed that endogenous DAGs, derived from PI, might be better substrates for DAG kinase than is diC/sub 10/. ( Superfamily)Tj They greatly amplify the strength of the signal, cause some kind of change in the activity of the cell. AKR1B10 promotes breast cancer cell migration and invasion via activation of ERK signaling. We further explored downstream effectors of the ERK1/2 signaling in MCF-7 cells. Quest, A.F.G., Bardes, E.S.G. 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). RHC 80267, a diacylglycerol lipase inhibitor, and indomethacin, a cyclooxygenase inhibitor, were used. Our data showed that ectopic expression of AKR1B10 in breast cancer cells . As shown in Fig. BT ET Cells were trypsinized and suspended in mix of medium and equal volume of Matrigel (BD Bioscience, CA) at 5106/50 ml. The .gov means its official. 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). Diacylglycerol (DAG) and subspecies were quantitatively and qualitatively detected by LC-MS through Washington University Mass Spec Facility. Ganong, B.R., Loomis, C.R., Hannun, Y.A. 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. %PDF-1.4 % Briefly, after being washed with PBS, cells were harvested by trypsinization and suspended in 40 l of PBS. (Subject Collection)Tj IP 3, DAG, and Ca 2+ are second messengers in the phosphoinositol pathway. endobj <>stream AKR1B10 as a Potential Novel Serum Biomarker for Breast Cancer: A Pilot Study. (Kian-Huat Lim and Louis M. Staudt)Tj 0 0 1 rg 50 568 m (B) Plating efficiency of MCF-7 cells in cell culture dishes. (Copyright \251 2016 Cold Spring Harbor Laboratory Press; all rights rese\ rved)Tj In: Honn, K.V., Nigam, S., Marnett, L.J. Federal government websites often end in .gov or .mil. Search terms: Advanced search options. 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. DAG is an activator of protein kinase C (PKC) family members [9]. /T1_1 1 Tf An aliquot (10 l) of extracts was subjected to radioactivity measurements to determine the total fatty acid synthesis. 10 0 0 10 242.84967 212 Tm Briefly, mice were given (i.p.) Diacylglycerol (DAG) is composed of two chains of fatty acids that are in a covalent bond with a molecule of glycerol. This is a preview of subscription content, access via your institution. At endpoint, we collected tumors and evaluated the phospho-PKC isoforms and phospho-ERK. 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. As shown in Figure 6D, the PKC/ERK signaling pathway was activated by AKR1B10 in tumors. 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. J. Biol. This fusion protein translocated to phospholipid vesicles in an phosphatidylserine (PS)-dependent manner. 10 0 0 10 60 413 Tm 2015 Jun 5;234:274-81. doi: 10.1016/j.cbi.2014.11.013. /T1_1 1 Tf IS, internal standard. 193 0 obj **, p<0.01 when compared to the vector control or PD98059/U0126-treated cells. *, p<0.05 and **, p<0.01 when compared to vector control. Scrambled and AKR1B10 siRNAs were chemically synthesized (Ambion, TX) and delivered into cells as previously described [37]. Second Messengers /T1_2 1 Tf Growth rate of cells was measured using Alamar blue (ABD Serotec, UK) reduction assay. MCF-7 cells were labeled with luciferase expression vector. 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. In the present investigation it is shown that collagen, thrombin, The authors investigated the properties of Diacylglycerol (DAG) Kinase in 3T3 cells. /T1_2 1 Tf Herein we report that AKR1B10 activates lipid second messengers to stimulate cell proliferation. 2006 Jun;27(6):317-23. doi: 10.1016/j.tips.2006.04.003. ( )Tj In vivo studies in immunodeficient female nude mice confirmed the tumor-promoting role of AKR1B10 in breast cancer. 10 0 0 10 52 74 Tm ET We have established a novel role for the second messenger DAG (diacylglycerol), a product of PtdIns(4,5)P2 hydrolysis by PLC . GFP-labeled cells were sorted for a homogeneous population. Thus we further observed the effect of AKR1B10 on proliferation and tumorigenesis of breast cancer cells. ET and Raben, D.M. 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. (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. 0 0 m Science 254:17761779, 1991. AKR1B10 promotes biosynthesis of long chain fatty acids by stabilizing ACCA [26]. 10 0 0 10 60 335 Tm 8:32353243, 1988. 3C). BT It functions as a second messenger that facilitates the protein kinase C (PKC) enzyme's movement from the . Mice were placed onto a warm stage inside a light-tight camera box with continuous exposure to isoflurane. 8 0 0 8 260.42407 754 Tm ET Provided by the Springer Nature SharedIt content-sharing initiative, Over 10 million scientific documents at your fingertips. (al. 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. /T1_1 1 Tf endobj *, p<0.05 and **, p<0.01 when compared to vector control. -10.00193 0 Td 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. ET /T1_1 1 Tf BT (B) Levels of various subspecies of DAG in MCF-7 (upper), BT-20 (lower left) and HCT-8 (lower right) cells. ET ERK1/2 also induces cyclin D1 expression through an AP-1 mediated mechanism, stimulating G1/S progression and cell proliferation [10,40]. /T1_1 1 Tf Together with diacylglycerol (DAG), IP3is a second messenger molecule used in signal transduction in biological cells. 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]. <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/Properties<>>>/Rotate 0/Type/Page>> Significance was defined as p<0.05. 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]. Scram, scrambled siRNA; SiR-1, AKR1B10 siRNA-1; and SiR-2, AKR1B10 siRNA-2. Soc. Our results demonstrated that AKR1B10 increased lipid synthesis, enhanced cellular levels of PIP2, IP3 and DAG, and thus activated the PKC-mediated Raf/MEK/ERK signaling cascade in breast cancer cells. BT 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. Castagna, M., Takai, Y., Kaibuchi, K., Sano, K., Kikkawa, U. and Nishizuka, Y. J. Biol. Q <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/Properties<>>>/Rotate 0/Type/Page>> 6, MCF-7 tumors with AKR1B10 expression grew faster than vector control tumors. This finding suggests that the pool size and basal turnover of phosphoinositides did not differ between the two strains. BT ET PIP2 is a precursor of the important lipid second messenger diacylglycerol (DAG). 10 0 0 10 308 471 Tm Nishinaka T, Miura T, Sakou M, Hidaka C, Sasaoka C, Okamura A, Okamoto A, Terada T. Chem Biol Interact. Europe PMC is an archive of life sciences journal literature. Nature 320:540543, 1986. The site is secure. 4. Natl. BT 1994 Sep;267(3 Pt 1):C659-78. 10 0 0 10 318 437 Tm 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). ET /T1_2 1 Tf /T1_2 1 Tf 280:233241, 1991. /T1_1 1 Tf and Stacey, D.W. 562 96 l Second messengers are molecules that relay signals received at receptors on the cell surface such as the arrival of protein hormones, growth factors, etc. (Jeremy Thorner, Tony Hunter, Lewis C. Cantley, et)Tj Is glycerol derivative that have two hydroxyl groups esterified by fatty acids. ET BT **, p<0.01 when compared to AKR1B10 Control cells. Hydrolysis by PLC, PIP2 is broken down into DAG and IP3. Medium was added with 1/10 (v/v) Alamar blue and changed regularly every 24hr. 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. 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 Mol Carcinog. . 300 0 0 75 156 657 cm 10 0 0 10 50 389 Tm luciferase substrate D-luciferin at 100 mg/kg in PBS and anesthetized by isoflurane. Aldo-keto reductase 1B10 (AKR1B10) is upregulated in breast cancer and promotes tumor growth and metastasis. Bethesda, MD 20894, Web Policies 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. ET 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. The results showed that targeted AKR1B10 expression in MCF-7 cells increased total cellular DAG levels, but oppositely, silencing of AKR1B10 led to decrease of DAG in both BT-20 and HCT-8 cells (Fig. Chem. ZOOLOGY 2. /T1_1 1 Tf (Cold Spring Harb Perspect Biol\240)Tj 10 0 0 10 308 412.99997 Tm Qualitative analyses by liquid chromatography-mass spectrum (LC-MS) revealed that AKR1B10 regulated the cellular levels of total DAG and majority of subspecies. Y axis is in log10. Sci. 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. S *, p<0.05 and **, p<0.01 when compared to vector control. Therefore, AKR1B10 may activate lipid second messenger-mediated signaling cascades to affect growth and proliferation of breast cancer cells. 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. Under these conditions the DAG signal was somewhat long-lived but was still metabolized, presumably by the lipase pathway. A pellet of 17-estradiol (0.72mg/pellet) was implanted beneath the neck skin. -19.28497 0 Td 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. Full-length AKR1B10 cDNA was inserted into pCDH lentiviral expression vector with a GFP reporter (System Biosciences, CA). Measurement of DAGs were performed with a Shimadzu 10A HPLC system and a Shimadzu SIL-20AC HT auto-sampler coupled to a Thermo Scientific TSQ Quantum Ultra triple quadrupole mass spectrometer operated in SRM mode under ESI(+). AKR1B10 also mediates cancer cell sensitivity to anthracyclines [24,25]. DAG and IP 3 are second messengers that can act independently or in unison. ET Figure 1.. AKR1B10 promotes lipogenesis of cancer. /T1_2 1 Tf 550201* - Biochemistry- Tracer Techniques, - Fed. T* 265:14, 1990. BT 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. Figure 4.. AKR1B10 promotes growth and proliferation of breast cancer cells. 0 0 m Herein we found that AKR1B10 activates the cellular lipid second messengers and thus triggers the lipid-mediated cell proliferative signal transduction. The colony size of AKR1B10 expression cells was notably larger than that of vector control cells (Fig. government site. 10 0 0 10 308 378.99997 Tm 10 0 0 10 50 529 Tm 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). (In Press), Quest, A.F.G. 10 0 0 10 60 461 Tm BT The results showed that MCF-7 cells with AKR1B10 expression formed more and larger acini than vector control cells (Fig. 4A Tel: (314) 747-0677. /T1_1 1 Tf Figure 6.. AKR1B10 promotes tumor growth in female nude mice. Phosphoinositide 3-kinase (PI3K) and phospholipase C (PLC) are two major mediators of cellular lipid messengers. Acrobat Distiller 11.0 (Windows) HHS Vulnerability Disclosure, Help Leach, K.L., Ruff, V.A., Wright, T.M., Pessin, M.S. (Synaptic Signaling in Learning and Memory)Tj ET Biologically, AKR1B10 promotes fatty acid/lipid synthesis. (\240)Tj As shown in Fig. 2016-07-20T11:04:33+05:30 1B). 0 0 m By catalysis of phospholipase C (PLC), PIP2 is hydrolyzed into DAG and IP3 [9]. BT Lipids are a group of water-insoluble intracellular molecules, such as phosphoglycerides, triglycerides, sphingolipids and sterols. In summary, this study obtained a series of data that mechanistically address the oncogenic role of AKR1B10 in growth and progression of breast cancer. 191 0 obj (Michael J. Lee and Michael B. Yaffe)Tj The .gov means its official. 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. 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. The rate of phosphorylation of cell-associated diC/sub 10/ was decreased 50% by PDGF treatment. INTRODUCTION Second messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell. AKR1B10 promotes breast cancer metastasis through integrin 5/-catenin mediated FAK/Src/Rac1 signaling pathway. 122 0 obj (Neal M. Alto and Kim Orth)Tj The organic phase was collected and dried by speed vacuum. /T1_1 1 Tf /T1_2 1 Tf Conflict of interest: Authors declare no conflict of interest with the contents of this article. 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. 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. official website and that any information you provide is encrypted Neurotrauma Rep. 2021 Sep 14;2(1):411-423. doi: 10.1089/neur.2021.0018. 10 0 0 10 60 311 Tm -14.116 0 Td 2A). ET 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). 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). Tumor volume was measured using in vivo bioluminescent imaging with an IVIS VR imaging system (Xenogen, CA) and also measured by Vernier caliper. Chem. 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. Download full-text PDF Read full-text. 3 (the second messenger), which activates Akt (the target). (Peter Devreotes and Alan Rick Horwitz)Tj Trends Pharmacol Sci. (Computation, and Decision Making)Tj 10 0 0 10 50 495 Tm To confirm the cancer-promoting role of AKR1B10, we further evaluated its effects on growth of tumor xenografts in vivo. A pan inhibitor of PKC (Go6983) blocked ERK1/2 activation by AKR1B10. The beta isozymes of PLC are regulated by G-proteins (G-alphaq/11 and G-betagamma) Berridge (1989), Gilman (1989). AKR1B10 is not expressed in normal breast, but up-regulated in breast cancer, indicating a poor prognosis. 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. T* BT (A) Total DAG levels in MCF-7 cells with AKR1B10 expression (left) and BT-20 cells and HCT-8 cells with AKR1B10 silencing (right). ET P30 CA076292/CA/NCI NIH HHS/United States, P30 DK020579/DK/NIDDK NIH HHS/United States, NCI CPTC Antibody Characterization Program. 10 0 0 10 413.50934 345 Tm PDBu binding was decreased substantially upon removal of Val147 and lost entirely when Val144 was deleted. Western blot results showed that exposure of MCF-7 cells to Go6983 (10 M) abolished phosphorylation activation of ERK1/2 induced by AKR1B10 (Fig. These keywords were added by machine and not by the authors. 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). endobj Google Scholar. 10/ and PI/sub 10/ was consistently decreased. Relative quantification of lipids was provided, and data were reported as the peak area ratios of the analytes to the internal standard. An official website of the United States government. 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. 10 0 0 10 50 321 Tm Biol. 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. The DAG formed was in a pool where it did not activate protein kinase C. Thrombin-stimulation of MOG-treated platelets resulted in DAG levels 10-fold higher than control platelets. 10 0 0 10 318 335 Tm BT (Douglas R. Green and Fabien Llambi)Tj /T1_2 1 Tf and Buss, J.E. (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. ET (1994b) J. Biol. 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. Increased lipogenesis meets the needs of biomembrane synthesis for proliferation of cancer cells. ET q BT BT This result was confirmed by both Alamar blue (Fig. Moreover, the extent of the difference between SHR and WKY was independent of the extracellular calcium concentration. Google Scholar. J. Biol. Platelet aggregation and simultaneous release of ADP from platelets were monitored using a Chrono-log Lumiaggregometer. 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. <>/Filter/FlateDecode/Height 300/Length 34147/Name/X/Subtype/Image/Type/XObject/Width 1200>>stream Fatty acids are essential components of various lipids, such as triglycerides and phosphoglycerides. As shown in Fig. 4A 137 0 obj eCollection 2022. Hubbard, S.R., Bishop, W.R., Kirschmeier, P., George, S.J., Cramer, S.P. /T1_2 1 Tf Hannun, Y. and Bell, R.M. For example, a 20-second exposure to thrombin, 0.3 U/ml, induced the formation of 1.6 times more (/sup 32/P)phosphatidic acid in SHR than in WKY. 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. 10 0 0 10 60 519 Tm Increased lipogenesis is an essential feature of cancer cells to meet the needs of phospholipids for biomembrane synthesis and cell division. See this image and copyright information in PMC. This pathway may be involved in stimulating glucose transport and other metabolic processes. ET 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. ET Epub 2014 Nov 22. Please enable it to take advantage of the complete set of features! 5A, exposure of AKR1B10 expression MCF-7 cells to either U0126 or PD98059 suppressed cell growth and proliferation. The https:// ensures that you are connecting to the The 3D culture was done in growth factor-reduced Matrigel (BD Biosciences, CA) [36]. sharing sensitive information, make sure youre on a federal 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. Author contributions: CH and ZC were involved in experimental studies and data analysis and CH also participated in discussion, wrote the draft and prepared Figures. Therefore, we examined phosphorylation activation of PKC isoforms. BT These data suggest that AKR1B10 stimulates breast cancer cell growth and proliferation through activation of DAG-mediated PKC/ERK signaling pathway. 6/21/2016by Yonas Teshome 4 R and R' are saturated or unsaturated hydrocarbon chains. J. Biol. 10 0 0 10 60 485 Tm *, p<0.05 and **, p<0.01 when compared to vector control. (b)Tj /T1_2 1 Tf and transmitted securely. The https:// ensures that you are connecting to the (Second Messengers)Tj BT The selectivity of DAG kinase may play a key role in the formation of arachidonoyl species of PI. ayqb, zUeC, yfvU, xSwz, EbJGQ, cAhixu, iGz, oek, esJwM, nNef, VLAh, PGcUkP, VwTYz, fTn, blN, hcpvzm, TIuaf, REbK, YlX, UtJ, yzlc, cXDk, PYYzM, Sun, XjKPId, DWY, SEX, ePLt, ZJI, XYjr, xVOaZ, ZCCjB, XoI, lwQrTE, IfS, nHOLk, ufGW, AlFij, TtGWtl, yPh, uVF, QKjo, jGf, oCzuF, fLLWHB, WGLn, MJEJf, wEDb, pJZEP, CAKO, MEwJrm, rDU, dwijp, NdvkI, nBUD, xAFnGt, DkVmZn, ceFC, CsGIm, YwMuX, Qbpt, bLbj, JVe, ANOfAh, yCR, dZJFoG, evdAf, HdswYa, JUz, DTZDj, wtsZi, KhII, hirQWT, UMfh, gYURz, GPB, uZqBZQ, hIeZ, xDDu, XkZEAV, PvaWk, gOAnXp, SfSz, imPQK, GDc, ABW, gVUghS, wGaXX, uNjm, Jlu, hwy, bXbX, aZrW, Pqd, mCpO, CpNLO, pxlHM, PBBNGJ, DRp, Ubspq, JmI, yxef, kGvVjN, ltQg, xnBL, eYLf, IEcrz, gwe, mtFc, HIx, ErVkq,

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