title: Inhibition of adipose triglyceride lipase (ATGL) by the putative tumor suppressor G0S2 or a small molecule inhibitor attenuates the growth of cancer cells.
abstract: The G0/G1 switch gene 2 (G0S2) is methylated and silenced in a wide range of human cancers. The protein encoded by G0S2 is an endogenous inhibitor of lipid catabolism that directly binds adipose triglyceride lipase (ATGL). ATGL is the rate-limiting step in triglyceride metabolism. Although the G0S2 gene is silenced in cancer, the impact of ATGL in the growth and survival of cancer cells has never been addressed. Here we show that ectopic expression of G0S2 in non-small cell lung carcinomas (NSCL) inhibits triglyceride catabolism and results in lower cell growth. Similarly, knockdown of ATGL increased triglyceride levels, attenuated cell growth and promoted apoptosis. Conversely, knockdown of endogenous G0S2 enhanced the growth and invasiveness of cancer cells. G0S2 is strongly induced in acute promyelocytic leukemia (APL) cells in response to all trans retinoic acid (ATRA) and we show that inhibition of ATGL in these cells by G0S2 is required for efficacy of ATRA treatment. Our data uncover a novel tumor suppressor mechanism by which G0S2 directly inhibits activity of a key intracellular lipase. Our results suggest that elevated ATGL activity may be a general property of many cancer types and potentially represents a novel target for chemotherapy.
authors: Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada.
authors: Rachid
authors: R
authors: Zagani
authors: Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada.
authors: Wissal
authors: W
authors: El-Assaad
authors: Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada.
authors: Isabelle
authors: I
authors: Gamache
authors: Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada.|Department of Biochemistry, McGill University, Montréal, QC, Canada.
authors: Jose G
authors: JG
authors: Teodoro
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008049:Lipase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology; D011485:Protein Binding; D034622:RNA Interference; D014212:Tretinoin / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000217:Acyltransferases
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D008049:Lipase; D010671:Phenylurea Compounds; D014212:Tretinoin; D014280:Triglycerides; D025521:Tumor Suppressor Proteins; C508073:G0S2 protein, human; C585749:atglistatin; C494794:PNPLA2 protein, human; D000217:Acyltransferases
keywords: ATGL; G0S2; lipase; lipids; metabolism; triglycerides; tumor suppressor