Adipose triglyceride lipase activity regulates cancer cell proliferation via AMP-kinase and mTOR signaling.
ATGL
Cancer
Lipid
Lipolysis
Proliferation
Journal
Biochimica et biophysica acta. Molecular and cell biology of lipids
ISSN: 1879-2618
Titre abrégé: Biochim Biophys Acta Mol Cell Biol Lipids
Pays: Netherlands
ID NLM: 101731727
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
09
12
2019
revised:
15
04
2020
accepted:
06
05
2020
pubmed:
15
5
2020
medline:
1
1
2021
entrez:
15
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32404277
pii: S1388-1981(20)30129-3
doi: 10.1016/j.bbalip.2020.158737
pmc: PMC7397471
pii:
doi:
Substances chimiques
TOR Serine-Threonine Kinases
EC 2.7.11.1
Adenylate Kinase
EC 2.7.4.3
Lipase
EC 3.1.1.3
PNPLA2 protein, human
EC 3.1.1.3
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
158737Subventions
Organisme : European Research Council
ID : 340896
Pays : International
Organisme : Austrian Science Fund FWF
ID : W 1226
Pays : Austria
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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