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

被引：70

作者：

Byun, Jun-Kyu ^{[1
,2
,4
]}

Choi, Yeon-Kyung ^{[2
,4
]}

Kim, Ji-Hyun ^{[2
,4
,7
]}

Jeong, Ji Yun ^{[3
]}

Jeon, Hui-Jeon ^{[4
]}

Kim, Mi-Kyung ^{[5
]}

Hwang, Ilseon ^{[6
]}

Lee, Shin-Yup ^{[2
]}

Lee, You Mie ^{[1
]}

Lee, In-Kyu ^{[2
,4
,7
]}

Park, Keun-Gyu ^{[2
,4
,7
]}

机构：

[1] Kyungpook Natl Univ, Res Inst Pharmaceut Sci, Coll Pharm, Daegu 41566, South Korea

[2] Kyungpook Natl Univ, Dept Internal Med, Sch Med, Daegu 41944, South Korea

[3] Kyungpook Natl Univ, Dept Pathol, Sch Med, Daegu 41944, South Korea

[4] Kyungpook Natl Univ, Sch Med, Leading Edge Res Ctr Diabet & Metab Dis, Daegu 41944, South Korea

[5] Keimyung Univ, Dept Internal Med, Sch Med, Daegu 41931, South Korea

[6] Keimyung Univ, Dept Pathol, Sch Med, Daegu 41931, South Korea

[7] Kyungpook Natl Univ, Sch Med, Res Inst Aging & Metab, Daegu 41944, South Korea

来源：

CELL REPORTS | 2017年 / 20卷 / 03期

基金：

新加坡国家研究基金会;

关键词：

SIGNAL INTEGRATION; METABOLISM; DEPRIVATION; PATHWAY; STRESS; GROWTH; AKT; PROLIFERATION; COMPLEX; BINDING;

D O I：

10.1016/j.celrep.2017.06.066

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：586 / 599

页数：14

共 30 条

[11] AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress [J].