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

• Published in: The Journal of biological chemistry 2021-01, Vol.296, p.100104-100104, Article 100104
• Main Authors: Chen, Guohua, Zhou, Guoli, Lotvola, Aaron, Granneman, James G., Wang, Jian
• Format: Article
• Language: English
• Subjects: 1-Acylglycerol-3-Phosphate O-Acyltransferase - genetics; 1-Acylglycerol-3-Phosphate O-Acyltransferase - metabolism; Adenosine Monophosphate - metabolism; Adenosine Triphosphate - metabolism; AMP-activated protein kinase (AMPK); AMP-Activated Protein Kinases - metabolism; Blotting, Western; cancer metabolism; Cell Cycle - genetics; Cell Cycle - physiology; Cell Proliferation - genetics; Cell Proliferation - physiology; Humans; lipolysis; Lipolysis - physiology; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolism - physiology; mTOR; RNA-Seq; αβ hydrolase domain containing 5 (ABHD5)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA120.014682

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.