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.

Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis

“…S3a-c). In line with previous studies [24][25][26] , we therefore hypothesized that the increased level of αKG could be the main mechanism perturbing autophagy and therefore promoting cell death in cystinotic proximal tubule cells. DMKG exposure indeed resulted in an increased level of LC3-II/LC3-I ratio in CTNS -/and CTNS Patient but not in control cells, confirming that αKG is a key metabolite abnormally inducing autophagy in cystinotic cells ( Fig.…”

Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer

“…Cancer is frequently a result of disrupted coordination between the suppressive signals from internal or external stresses and the stimulating signals from growth factors and nutrients (34). The mTOR signaling is a key regulator involved in many facets of carcinogenic and metabolic events, including autophagy, apoptosis (35)(36)(37)(38)(39)(40)(41), migration and invasion (42), differentiation, energy metabolism, and inflammation (43). Autophagy is a stress-responsive catabolic process followed by lysosomal degradation of intracellular components (44), removing aggregated protein, damaged organelles, and pathogen clearance, in order to provide energy for normal cellular function.…”

Novel therapeutic roles of MC‐4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinase muscle isozyme M2 and mechanistic target of rapamycin complex 1 pathways

“…For example, dual targeting of autophagic regulation with autophagy enhancers produced therapeutic benefits via cytotoxic autophagic flux in glioma . As mTORC1 complex is currently considered the autophagy master switch acting like a sensor of nutrient levels to promote proliferation and inhibit autophagy by signaling to the Unc‐51 like autophagy activating kinase 1 (ULK1) complex, mTORC1 inhibitors have been shown to induce autophagy in tumor cells . Pharmacologic blockage of mTORC1 can mimic starvation and promote dissociation of mTORC1 from the complex of ATG13 with ULK1 and ULK2, thereby leaving ULK1‐2 free to initiate autophagy .…”

“…34 As mTORC1 complex is currently considered the autophagy master switch acting like a sensor of nutrient levels to promote proliferation and inhibit autophagy by signaling to the Unc-51 like autophagy activating kinase 1 (ULK1) complex, 37 mTORC1 inhibitors have been shown to induce autophagy in tumor cells. [38][39][40] Pharmacologic blockage of mTORC1 can mimic starvation and promote dissociation of mTORC1 from the complex of ATG13 with ULK1 and ULK2, thereby leaving ULK1-2 free to initiate autophagy. 38 Based on these rationales, several early phase clinical trials are ongoing to evaluate the safety and activity of combined autophagy-mTOR inhibition.…”