A Positive Feedback Loop between Sestrin2 and mTORC2 Is Required for the Survival of Glutamine-Depleted Lung Cancer Cells

Highlights•Induction of Sestrin2 is critical for glutamine-depleted lung cancer cell survival•Glutamine depletion creates a positive feedback loop between Sestrin2 and mTORC2•Differential regulation of mTORC1 and 2 by Sestrin2 maintains ATP and redox balance•Co-targeting SLC1A5 and Sestrin2 is a promising therapeutic strategy for lung cancerSummaryProper regulation of mTORC1 and mTORC2 upon nutrient starvation is critical for cancer cell survival. Upregulation of Sestrin2 in response to glutamine deprivation rescues cell death by suppressing mTORC1. However, the contribution of mTORC2 to Sestrin2-mediated mTORC1 suppression remains unclear. Here, we report that both Sestrin2 and mTORC2 are upregulated in glutamine-depleted lung cancer cells. Moreover, glutamine depletion caused Sestrin2 to associate with mTORC2, which was required for the increase in Sestrin2 protein stability and the reduction in mTORC1 activity. Ultimately, differential regulation of mTORC1 and 2 by Sestrin2 reprogramed lipid metabolism and enabled glutamine-depleted lung cancer cells to survive by maintaining energy and redox balance. Importantly, combined inhibition of glutamine utilization and Sestrin2 induced lung cancer cell death both in vitro and in vivo. This study shows that differential Sestrin2-mediated regulation of mTORC1 and mTORC2 is necessary for the survival of glutamine-depleted lung cancer cells.Graphical abstract