Adipose triglyceride lipase activity regulates cancer cell proliferation via AMP-kinase and mTOR signaling.

Abstract

Aberrant fatty acid (FA) metabolism is a hallmark of proliferating cells, including untransformed fibroblasts or cancer cells. Lipolysis of intracellular triglyceride (TG) stores by adipose triglyceride lipase (ATGL) provides an important source of FAs serving as energy substrates, signaling molecules, and precursors for membrane lipids. To investigate if ATGL-mediated lipolysis impacts cell proliferation, we modified ATGL activity in murine embryonic fibroblasts (MEFs) and in five different cancer cell lines to determine the consequences on cell growth and metabolism. Genetic or pharmacological inhibition of ATGL in MEFs causes impaired FA oxidation, decreased ROS production, and a substrate switch from FA to glucose leading to decreased AMPK-mTOR signaling and higher cell proliferation rates. ATGL expression in these cancer cells is low when compared to MEFs. Additional ATGL knockdown in cancer cells did not significantly affect cellular lipid metabolism or cell proliferation whereas the ectopic overexpression of ATGL increased lipolysis and reduced proliferation. In contrast to ATGL silencing, pharmacological inhibition of ATGL by Atglistatin© impeded the proliferation of diverse cancer cell lines, which points at an ATGL-independent effect. Our data indicate a crucial role of ATGL-mediated lipolysis in the regulation of cell proliferation. The observed low ATGL activity in cancer cells may represent an evolutionary selection process and mechanism to sustain high cell proliferation rates. As the increasing ATGL activity decelerates proliferation of five different cancer cell lines this may represent a novel therapeutic strategy to counteract uncontrolled cell growth.

• Authors: Hao Xie, Christoph Heier, Benedikt Kien, Paul W Vesely, Zhiyuan Tang, Veronika Sexl, Gabriele Schoiswohl, Isabelle Strießnig-Bina, Gerald Hoefler, Rudolf Zechner, Martina Schweiger
• Journal: Biochimica et biophysica acta. Molecular and cell biology of lipids (Biochim Biophys Acta Mol Cell Biol Lipids) Vol. 1865 Issue 9 Pg. 158737 (09 2020) ISSN: 1879-2618 [Electronic] Netherlands
• PMID: 32404277 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• TOR Serine-Threonine Kinases
• Adenylate Kinase
• Lipase
• PNPLA2 protein, human

Topics

• Adenylate Kinase (metabolism)
• Animals
• Cell Line
• Cell Proliferation
• Fibroblasts (metabolism)
• Humans
• Lipase (metabolism)
• Lipolysis
• Mice
• Neoplasms (metabolism, pathology)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)