mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation
- PMID: 28112156
- PMCID: PMC5264013
- DOI: 10.1038/ncomms14124
mTORC1 inhibition in cancer cells protects from glutaminolysis-mediated apoptosis during nutrient limitation
Abstract
A master coordinator of cell growth, mTORC1 is activated by different metabolic inputs, particularly the metabolism of glutamine (glutaminolysis), to control a vast range of cellular processes, including autophagy. As a well-recognized tumour promoter, inhibitors of mTORC1 such as rapamycin have been approved as anti-cancer agents, but their overall outcome in patients is rather poor. Here we show that mTORC1 also presents tumour suppressor features in conditions of nutrient restrictions. Thus, the activation of mTORC1 by glutaminolysis during nutritional imbalance inhibits autophagy and induces apoptosis in cancer cells. Importantly, rapamycin treatment reactivates autophagy and prevents the mTORC1-mediated apoptosis. We also observe that the ability of mTORC1 to activate apoptosis is mediated by the adaptor protein p62. Thus, the mTORC1-mediated upregulation of p62 during nutrient imbalance induces the binding of p62 to caspase 8 and the subsequent activation of the caspase pathway. Our data highlight the role of autophagy as a survival mechanism upon rapamycin treatment.
Figures






Similar articles
-
Pharmacological inhibition of mTORC1 but not mTORC2 protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism through Akt and autophagy induction.Osteoarthritis Cartilage. 2019 Jun;27(6):965-976. doi: 10.1016/j.joca.2019.01.009. Epub 2019 Feb 1. Osteoarthritis Cartilage. 2019. PMID: 30716534
-
Selective interference of mTORC1/RAPTOR protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism with Akt and autophagy induction.Osteoarthritis Cartilage. 2017 Dec;25(12):2134-2146. doi: 10.1016/j.joca.2017.08.019. Epub 2017 Sep 6. Osteoarthritis Cartilage. 2017. PMID: 28888905
-
Glutamoptosis: A new cell death mechanism inhibited by autophagy during nutritional imbalance.Autophagy. 2017 Jun 3;13(6):1078-1079. doi: 10.1080/15548627.2017.1299315. Epub 2017 Mar 15. Autophagy. 2017. PMID: 28296535 Free PMC article.
-
The anticancer effects of curcumin via targeting the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway.Pharmacol Res. 2020 Jun;156:104798. doi: 10.1016/j.phrs.2020.104798. Epub 2020 Apr 8. Pharmacol Res. 2020. PMID: 32278045 Review.
-
Glutaminolysis and autophagy in cancer.Autophagy. 2015;11(8):1198-208. doi: 10.1080/15548627.2015.1053680. Autophagy. 2015. PMID: 26054373 Free PMC article. Review.
Cited by
-
Glutamine addiction in tumor cell: oncogene regulation and clinical treatment.Cell Commun Signal. 2024 Jan 3;22(1):12. doi: 10.1186/s12964-023-01449-x. Cell Commun Signal. 2024. PMID: 38172980 Free PMC article. Review.
-
PD-L1 regulates tumorigenesis and autophagy of ovarian cancer by activating mTORC signaling.Biosci Rep. 2019 Dec 20;39(12):BSR20191041. doi: 10.1042/BSR20191041. Biosci Rep. 2019. PMID: 31799599 Free PMC article.
-
Pharmacological inhibition of mTORC1 activity protects against inflammation-induced apoptosis of nucleus pulposus cells.Braz J Med Biol Res. 2021 Mar 15;54(5):e10185. doi: 10.1590/1414-431X202010185. eCollection 2021. Braz J Med Biol Res. 2021. PMID: 33729389 Free PMC article.
-
Limiting glutamine utilization activates a GCN2/TRAIL-R2/Caspase-8 apoptotic pathway in glutamine-addicted tumor cells.Cell Death Dis. 2022 Oct 27;13(10):906. doi: 10.1038/s41419-022-05346-y. Cell Death Dis. 2022. PMID: 36302756 Free PMC article.
-
The transcription factor MZF1 differentially regulates murine Mtor promoter variants linked to tumor susceptibility.J Biol Chem. 2019 Nov 8;294(45):16756-16764. doi: 10.1074/jbc.RA119.009779. Epub 2019 Sep 23. J Biol Chem. 2019. PMID: 31548308 Free PMC article.
References
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials