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

The Journal of Biological Chemistry
Guohua ChenJian Wang

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, l...Continue Reading

References

Aug 26, 1999·In Vitro Cellular & Developmental Biology. Animal·R M SramkoskiJ W Jacobberger
Oct 17, 2001·The Journal of Clinical Investigation·G ZhouD E Moller
Jun 6, 2003·The Journal of Biological Chemistry·Lea ReshefRichard W Hanson
Jul 24, 2007·Bioinformatics·Aravind SubramanianJill P Mesirov
May 23, 2009·Science·Matthew G Vander HeidenCraig B Thompson
Dec 14, 2011·Proceedings of the National Academy of Sciences of the United States of America·Jing LiuAdrian Salic
Apr 17, 2012·Cell·Mathieu Laplante, David M Sabatini
Jun 25, 2013·Cell Metabolism·Erin CurrieRobert V Farese
Oct 26, 2013·Nature Protocols·F Ann RanFeng Zhang
May 12, 2011·ACS Medicinal Chemistry Letters·Robert L DowPaul DaSilva-Jardine
Jan 22, 2015·EMBO Molecular Medicine·Rudolf Zechner
Sep 9, 2015·Journal of Medicinal Chemistry·Kentaro FutatsugiBryan Goodwin
Jan 15, 2016·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Issan ZhangDusica Maysinger
Aug 3, 2017·Cell Metabolism·Chandramohan ChitrajuRobert V Farese
Sep 21, 2017·The Journal of Pharmacology and Experimental Therapeutics·Elizabeth A RondiniJames G Granneman
Dec 13, 2017·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Eva JarcToni Petan
Feb 24, 2018·Cell Death & Disease·Rolando VeglianteMaria Rosa Ciriolo
Mar 5, 2020·Cell Metabolism·Asier GonzálezD Grahame Hardie

❮ Previous
Next ❯

Software Mentioned

ImageJ
FastQC
CASAVA
STAR
Illumina
edgeR
QuantSeq
GSEA

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.