ABHD5 suppresses cancer cell anabolism through lipolysis-dependent activation of the AMPK/mTORC1 pathway

Abstract

ABHD5 is an essential coactivator of ATGL, the rate-limiting triglyceride (TG) lipase in many cell types. Importantly, ABHD5 also functions as a tumor suppressor, and ABHD5 mRNA expression levels correlate with patient survival for several cancers. Nevertheless, the mechanisms involved in ABHD5-dependent tumor suppression are not known. We found that overexpression of ABHD5 induces cell cycle arrest at the G1 phase and causes growth retardation in a panel of prostate cancer cells. Transcriptomic profiling and biochemical analysis revealed that genetic or pharmacological activation of lipolysis by ABHD5 potently inhibits mTORC1 signaling, leading to a significant downregulation of protein synthesis. Mechanistically, we found that ABHD5 elevates intracellular AMP content, which activates AMPK, leading to inhibition of mTORC1. Interestingly, ABHD5-dependent suppression of mTORC1 was abrogated by pharmacological inhibition of DGAT1 or DGAT2, isoenzymes that re-esterify fatty acids in a process that consumes ATP. Collectively, this study maps out a novel molecular pathway crucial for limiting cancer cell proliferation, in which ABHD5-mediated lipolysis creates an energy-consuming futile cycle between TG hydrolysis and resynthesis, leading to inhibition of mTORC1 and cancer cell growth arrest. ABHD5 is an essential coactivator of ATGL, the rate-limiting triglyceride (TG) lipase in many cell types. Importantly, ABHD5 also functions as a tumor suppressor, and ABHD5 mRNA expression levels correlate with patient survival for several cancers. Nevertheless, the mechanisms involved in ABHD5-dependent tumor suppression are not known. We found that overexpression of ABHD5 induces cell cycle arrest at the G1 phase and causes growth retardation in a panel of prostate cancer cells. Transcriptomic profiling and biochemical analysis revealed that genetic or pharmacological activation of lipolysis by ABHD5 potently inhibits mTORC1 signaling, leading to a significant downregulation of protein synthesis. Mechanistically, we found that ABHD5 elevates intracellular AMP content, which activates AMPK, leading to inhibition of mTORC1. Interestingly, ABHD5-dependent suppression of mTORC1 was abrogated by pharmacological inhibition of DGAT1 or DGAT2, isoenzymes that re-esterify fatty acids in a process that consumes ATP. Collectively, this study maps out a novel molecular pathway crucial for limiting cancer cell proliferation, in which ABHD5-mediated lipolysis creates an energy-consuming futile cycle between TG hydrolysis and resynthesis, leading to inhibition of mTORC1 and cancer cell growth arrest. The proliferation of cancer cells requires a robust synthesis of macromolecules, anabolism, which is essential for the rapid duplication of biomass in the aggressive production of daughter cells. In this regard, proliferating cancer cells usually expand cytosolic glycolysis and repress mitochondrial oxidation so that the carbon skeleton of glucose can be diverted to the anabolic pathways efficiently (1Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (9123) Google Scholar). Despite limited mitochondrial oxidative capacity, robust aerobic glycolysis allows cancer cells to synthesize sufficient ATP to meet the energy needs for proliferation (1Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (9123) Google Scholar). Although the “glucose addiction” of cancer cells is well known, less appreciated is that during rapid cell division, cancer metabolism is often reprogrammed to suppress the utilization of other energy substrates, such as fatty acid (FA), that require mitochondrial oxidation to generate ATP. Such rewiring of metabolic dependency in cancer could represent an unappreciated vulnerability that might be targeted therapeutically. When cancer cells proliferate under the conditions of high glycolytic flux, FAs are not used as energy substrates and may even be incompatible with fulfilling the energy need for cancer anabolism (2Currie E. Schulze A. Zechner R. Walther T.C. Farese Jr., R.V. Cellular fatty acid metabolism and cancer.Cell Metab. 2013; 18: 153-161Abstract Full Text Full Text PDF PubMed Scopus (989) Google Scholar). In this regard, many cancers are known to accumulate excessive amounts of intracellular triglycerides (TG) in lipid droplets (LD) (3Jarc E. Kump A. Malavašič P. 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Epigenetic downregulation of the ISG15–conjugating enzyme UbcH8 impairs lipolysis and correlates with poor prognosis in nasopharyngeal carcinoma.Oncotarget. 2015; 6: 41077Crossref PubMed Scopus (22) Google Scholar, 16Ou J. Miao H. Ma Y. Guo F. Deng J. Wei X. Zhou J. Xie G. Shi H. Xue B. Loss of Abhd5 promotes colorectal tumor development and progression by inducing aerobic glycolysis and epithelial-mesenchymal transition.Cell Rep. 2014; 9: 1798-1811Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 17Chen G. Zhou G. Aras S. He Z. Lucas S. Podgorski I. Skar W. Granneman J.G. Wang J. Loss of ABHD5 promotes the aggressiveness of prostate cancer cells.Sci. Rep. 2017; 7: 13021Crossref PubMed Scopus (20) Google Scholar). Moreover, we and others have demonstrated that ABHD5, the crucial lipolysis activator, actively participates in tumor suppression (16Ou J. Miao H. Ma Y. Guo F. Deng J. Wei X. Zhou J. Xie G. Shi H. Xue B. Loss of Abhd5 promotes colorectal tumor development and progression by inducing aerobic glycolysis and epithelial-mesenchymal transition.Cell Rep. 2014; 9: 1798-1811Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 17Chen G. Zhou G. Aras S. He Z. Lucas S. Podgorski I. Skar W. Granneman J.G. Wang J. Loss of ABHD5 promotes the aggressiveness of prostate cancer cells.Sci. Rep. 2017; 7: 13021Crossref PubMed Scopus (20) Google Scholar). While it is clear that activation of the ABHD5/ATGL pathway suppresses cancer cell growth, the mechanisms involved are not fully understood. The mechanistic target of rapamycin (mTOR) kinase plays a fundamental role in promoting cellular anabolism and is often hyperactive in cancer cells (18Laplante M. Sabatini D.M. mTOR signaling in growth control and disease.Cell. 2012; 149: 274-293Abstract Full Text Full Text PDF PubMed Scopus (5668) Google Scholar). mTOR is associated with two protein complexes, namely mTOR complex 1 (mTORC1) and mTORC2, which have distinct functional outputs in the regulation of cell signaling (18Laplante M. Sabatini D.M. mTOR signaling in growth control and disease.Cell. 2012; 149: 274-293Abstract Full Text Full Text PDF PubMed Scopus (5668) Google Scholar). mTORC1 phosphorylates numerous molecular components that are crucial for activating various biosynthetic pathways. For example, mTORC1 phosphorylates p70S6K kinase at threonine 389 (Thr389) to activate cellular protein synthesis. On the other hand, mTORC2 plays a critical role in finetuning mTOR signaling by phosphorylating a crucial upstream kinase protein kinase B (Akt) (18Laplante M. Sabatini D.M. mTOR signaling in growth control and disease.Cell. 2012; 149: 274-293Abstract Full Text Full Text PDF PubMed Scopus (5668) Google Scholar). Because anabolism is an energy-dependent process, mechanisms exist to restrict mTORC1 activity when energy levels are limiting. Under these conditions, AMP-activated protein kinase (AMPK), the cellular energy sensor, phosphorylates and inhibits mTORC1 activity (19González A. Hall M.N. Lin S.-C. Hardie D.G. AMPK and TOR: the Yin and Yang of cellular nutrient sensing and growth control.Cell Metab. 2020; 31: 472-492Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). The metabolites generated by ABHD5/ATGL play a crucial role in the maintenance of energy homeostasis. However, it is presently unclear whether and how lipolysis influences cancer metabolic signaling, mTOR and AMPK signaling pathways. In the we the of genetic and activation of ABHD5 on cancer cell We that growth arrest is by ATGL and is associated with inhibition of protein synthesis. Mechanistically, lipolysis activation to the process of which elevates AMP and activates a critical between the metabolic and signaling pathways that cancer growth and the vulnerability of cancer cells to activation of the ABHD5/ATGL metabolic ABHD5 can be targeted by F. L. H. X. M. J.A. G. and ABHD5 and lipolysis in and Metab. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar, L. Granneman J.G. pharmacological ABHD5 as a of lipolysis control in and 2017; PubMed Scopus Google Scholar), these an cancer pharmacological activation of ABHD5-mediated the of ABHD5 on cancer cell growth, we ABHD5 overexpression in two prostate cancer cell S. D. A human prostate cell Biol. PubMed Scopus Google and cells A. M. S. progression of human prostate cancer: and PubMed Scopus Google Scholar), under the control of a cell are as and of the and cells the cellular levels of ABHD5 protein and the levels of ATGL ABHD5 reduced the cellular TG of cell we the ABHD5 on cell growth by the cell of and cells in the or of a on the growth of the and cell not Interestingly, ABHD5 expression proliferation of cell a We also the inhibition of cell proliferation by ABHD5 overexpression in an prostate cancer cell cells the mechanistic how ABHD5 suppresses cell proliferation, we the cell cycle of the cells of ABHD5 for the G1 phase cell from to for and from to for and the phase cell from to for and from to for and ABHD5 cellular levels of However, ABHD5 overexpression not to that ABHD5 a for inducing G1 cell cycle arrest in prostate cancer in from activation of the tumor the molecular by which ABHD5 inhibits the proliferation of cancer we the of cells in the and of analysis A. H. J. P. J.P. a for PubMed Scopus Google Scholar), we the critical molecular pathways that are by ABHD5 We found that ABHD5 expression the signaling and mTORC1 signaling pathways the activity of these we the of and p70S6K at the two signaling In and we found that ABHD5 the of p70S6K at a molecular the mTORC1 or of that the of activity and the mTORC2 (18Laplante M. Sabatini D.M. mTOR signaling in growth control and disease.Cell. 2012; 149: 274-293Abstract Full Text Full Text PDF PubMed Scopus (5668) Google Scholar). the of ABHD5 suppresses the mTORC1 activity on the A functional of the mTORC1 signaling in activation of anabolic activation of protein synthesis. We used the J. Y. D. A. protein synthesis in cells and with an of S. A. 2012; PubMed Scopus Google to cellular synthesis of We found that ABHD5 by the these that the of ABHD5 expression suppresses mTORC1 signaling and inhibits cellular protein synthesis. ABHD5 is well known to the ATGL TG lipase and lipolysis R. and of intracellular Mol. 2015; 7: PubMed Scopus (38) Google Scholar). We ATGL to whether activity is involved in the mTORC1 suppression by The that of two for ATGL the of ATGL protein by with on the of ABHD5 protein in and cells of ATGL the downregulation of cellular TG by ABHD5 overexpression Importantly, of ATGL the downregulation of p70S6K by ABHD5 a on ATGL by ABHD5 to mTORC1. is a of ABHD5 that potently activates lipolysis F. L. H. X. M. J.A. G. and ABHD5 and lipolysis in and Metab. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar, L. Granneman J.G. pharmacological ABHD5 as a of lipolysis control in and 2017; PubMed Scopus Google Scholar). of cells with suppressed p70S6K in a the of ABHD5, we generated of cells with targeted of ABHD5 the this we that the of ABHD5 reduced the downregulation of p70S6K by in the two cell generated with Collectively, activation of ABHD5-mediated lipolysis, or mTORC1 signaling and inhibits the anabolism of cancer cells. is associated with the regulation of energy homeostasis R. and of intracellular Mol. 2015; 7: PubMed Scopus (38) Google Scholar). We the intracellular ATP and AMP in the cells with or ABHD5 The that the ATP in the the AMP leading to a significant of overexpression of ABHD5 as by at we the of on the energy of the cells. The that the of cells with a of intracellular AMP and the levels of in with the of genetic or activation of ABHD5 induces energy and activates The FAs from lipolysis may mitochondrial which promotes ATP synthesis and enhances cellular energy In the FAs can be TG in a process cellular energy L. Y. H. B. and the acid Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). We used to how these metabolic pathways link lipolysis activity to the of cellular energy and Inhibition of mitochondrial oxidation with a from fatty of in Res. PubMed Scopus Google on the cellular ATP and AMPK activation by ABHD5 overexpression in cells that lipid oxidation may be a to energy production in these cells. However, inhibition of by DGAT1 or Li J. S. E. A. of a and of PubMed Scopus Google or K. S. D. G. S. J. M. M. W. and of of acyltransferase 2 2015; PubMed Scopus Google the activation of AMPK by ABHD5 or in and cells. that AMPK activation and that a futile cycle hydrolysis and of TG cellular energy and activates AMPK signaling in to lipolysis activation in these cancer cells. AMPK inhibits cellular anabolism the of mTORC1 signaling (19González A. Hall M.N. Lin S.-C. Hardie D.G. AMPK and TOR: the Yin and Yang of cellular nutrient sensing and growth control.Cell Metab. 2020; 31: 472-492Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). the that AMPK ABHD5-dependent inhibition of we used G. R. Li Y. Chen Y. X. J. M. J. T. of AMP-activated protein kinase in of PubMed Scopus Google to AMPK in and cells. We that the of the suppression of ABHD5 on p70S6K and protein as by that AMPK activation lipolysis activity to the suppression of mTORC1 signaling and anabolic metabolism in these cancer cells. Collectively, these a novel which activation of ABHD5 inhibits cancer anabolism by a futile cycle of TG hydrolysis and synthesis that activates AMPK and inhibits mTORC1. The a of activation of ABHD5-mediated lipolysis in the of cancer this we whether ABHD5 expression levels with cancer patient survival in the the B. P. J. A. survival analysis to the of in 2013; PubMed Scopus Google Scholar). Interestingly, the of cancer in the we found that high ABHD5 expression correlates with patient survival in cancer cancer cancer cancer and ovarian cancer ABHD5 in the cancer cell we that ABHD5 the of these cells to synthesize which that ABHD5 suppresses the cellular anabolism of cancer in to the prostate cancer cells. Collectively, these that ABHD5 patient in cancer and that activation of ABHD5 may represent a these cancers. We and others demonstrated that loss of ABHD5 promotes aerobic glycolysis and and of prostate and colorectal cancer cells (16Ou J. Miao H. Ma Y. Guo F. Deng J. Wei X. Zhou J. Xie G. Shi H. Xue B. Loss of Abhd5 promotes colorectal tumor development and progression by inducing aerobic glycolysis and epithelial-mesenchymal transition.Cell Rep. 2014; 9: 1798-1811Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 17Chen G. Zhou G. Aras S. He Z. Lucas S. Podgorski I. Skar W. Granneman J.G. Wang J. Loss of ABHD5 promotes the aggressiveness of prostate cancer cells.Sci. Rep. 2017; 7: 13021Crossref PubMed Scopus (20) Google Scholar). of ATGL, the target of ABHD5, cell proliferation and (16Ou J. Miao H. Ma Y. Guo F. Deng J. Wei X. Zhou J. Xie G. Shi H. Xue B. Loss of Abhd5 promotes colorectal tumor development and progression by inducing aerobic glycolysis and epithelial-mesenchymal transition.Cell Rep. 2014; 9: 1798-1811Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 17Chen G. Zhou G. Aras S. He Z. Lucas S. Podgorski I. Skar W. Granneman J.G. Wang J. Loss of ABHD5 promotes the aggressiveness of prostate cancer cells.Sci. Rep. 2017; 7: 13021Crossref PubMed Scopus (20) Google Scholar), a critical of whether ABHD5 and ATGL can to cancer cell Although ABHD5 is an essential for TG lipase ATGL, it was unclear whether the cancer suppression by ABHD5 activity the signaling pathways we that ABHD5 mTORC1 signaling in an in suppression of protein synthesis and G1 cell cycle arrest. demonstrated that of ATGL or lipase in signaling and glucose in metabolic T. M. Wang Y. activates to mitochondrial for in Metab. 2013; 18: Full Text Full Text PDF PubMed Scopus Google Scholar, A. G. C. C. M. B. A. M. inhibition of adipose lipolysis glucose metabolism and of Biol. 2013; PubMed Scopus Google Scholar). adipose of ATGL and in in with a C. Wang Yang H. B. R. G. between the and causes in 2017; PubMed Scopus Google Scholar). is that lipolysis can as a functional anabolic pathways at and Collectively, not revealed the mechanisms the inhibition of cell proliferation by ABHD5 also the of cancer by activation of are often with as with In to the associated with excessive the study revealed a functional role of the in the suppression of cancer cell a significant of FAs in the of intracellular TG is an of cancer cells that are to lipolysis a for ABHD5-mediated lipolysis F. L. H. X. M. J.A. G. and ABHD5 and lipolysis in and Metab. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar, L. Granneman J.G. pharmacological ABHD5 as a of lipolysis control in and 2017; PubMed Scopus Google Scholar), we demonstrated that pharmacological activation of ABHD5 potently inhibits the signaling for cancer cell a of the for cancer by of In this regard, the of cancer patient survival revealed that high ABHD5 expression is associated with prognosis in cancer that ABHD5 activation might be an in a of cancer ABHD5-mediated lipolysis mTORC1 signaling is an mechanistic Because lipolysis FAs as energy substrates, an be that ABHD5-mediated lipolysis cellular energy and metabolic Indeed, we that ABHD5 activation induces cellular AMP accumulation and AMPK activation that is for mTORC1 We AMPK as a crucial the between ABHD5 and mTORC1. Interestingly, these a novel by which activation of lipolysis energy to the of anabolic in cancer cells. lipolysis in a significant of is to TG by L. Y. H. B. and the acid Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). Because requires between TG hydrolysis and energy and C. S. Walther T.C. Farese Jr., R.V. synthesis by DGAT1 from during Metab. 2017; 26: Full Text Full Text PDF PubMed Scopus Google Scholar, H. A.K. AMP-activated protein kinase is as a of lipolysis in the and Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). we demonstrated that the AMPK activation by ABHD5 is to the inhibition of that an energy-consuming futile cycle of and is for AMP accumulation and AMPK activation of ABHD5 activation in cancer cells. However, FAs from lipolysis can mitochondrial oxidation and ATP is presently unclear how the of between TG synthesis and mitochondrial oxidation is cells Warburg metabolism have reduced mitochondrial oxidative capacity, which may a of to the TG synthesis in ATP In this regard, the for of the metabolic that the of in cancer cells. Human prostate cancer cell and in with and of and of cells and human cancer cell in with and of and of For pharmacological of the was L. Granneman J.G. pharmacological ABHD5 as a of lipolysis control in and 2017; PubMed Scopus Google Scholar), and and from For overexpression of ABHD5, the was as G. Zhou G. Aras S. He Z. Lucas S. Podgorski I. Skar W. Granneman J.G. Wang J. Loss of ABHD5 promotes the aggressiveness of prostate cancer cells.Sci. Rep. 2017; 7: 13021Crossref PubMed Scopus (20) Google Scholar). For overexpression of ABHD5, the the human ABHD5 was with an and the of a with the of the with a For of the human ABHD5, the a J. V. F. the 2013; PubMed Scopus Google Scholar). The that and a from by the to a The of for ABHD5 are and For was with and cells and cell by For overexpression of ABHD5, and cells with and with For overexpression of ABHD5, cells with and with 2 For of ABHD5, cells with and with 5 The cells for ABHD5 expression by in and in 2 with the Cell by and The with and with ABHD5 ATGL Cell Cell Cell Cell Cell p70S6K Cell Cell Cell a with containing the with The protein by The on an and the protein the on and for the in the or of 2 The cells with and the of cells was with a under a For the of cellular content, cells in and with 5 and intracellular cells and in Cell with two of 5 and 5 by a at for 5 Cellular with TG on a to the cellular was the and for by the to the The a and to the at the and with to and the to the human and the expression was The to with the The pathway analysis was the with the on from the with for two and in on in of in and at cell was by at at for The metabolites on a and in the ATP was the ATP AMP was a from a a A of Google Scholar). 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