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.
Highlights
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
The mechanistic target of rapamycin kinase plays a fundamental role in promoting cellular anabolism and is often hyperactive in cancer cells [18]. mTOR is associated with two protein complexes, namely mTOR complex 1 and mTORC2, which have distinct functional outputs in the regulation of cell signaling [18]. mTORC1 phosphorylates numerous molecular components that are crucial for activating various biosynthetic pathways
We report that ABHD5-induced growth arrest is mediated by adipose triglyceride lipase (ATGL) and is associated with inhibition of mTORC1-mediated protein synthesis
Summary
Jian Wang1,* From the 1Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan, USA; 2Biomedical Research Informatics Core, Clinical and Translational Sciences Institute, Michigan State University, East Lansing, Michigan, USA; and 3Department of Oncology and 4Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA
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