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

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Jun-Kyu Byun, Yeon-Kyung Choi, Ji-Hyun Kim, Ji Yun Jeong, Hui-Jeon Jeon, Mi-Kyung Kim, Ilseon Hwang, Shin-Yup Lee, You Mie Lee, In-Kyu Lee, Keun-Gyu Park
Proper 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

Teaser

Byun et al. find that a positive feedback loop between Sestrin2 and mTORC2 is necessary to suppress mTORC1 activity in glutamine-depleted lung cancer cells. Differential regulation of mTORC1 and mTORC2 by Sestrin2 prevents ATP depletion and maintains redox balance, enabling lung cancer cells to survive under glutamine-depleted conditions.


http://ift.tt/2uxZNeA