Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase

被引：190

作者：

Gwinn, Dana M. ^{[1
,5
]}

Lee, Alex G. ^{[1
,5
]}

Briones-Martin-del-Campo, Marcela ^{[5
]}

Conn, Crystal S. ^{[2
,3
]}

Simpson, David R. ^{[1
,5
]}

Scott, Anna I. ^{[4
]}

Le, Anthony ^{[4
]}

Cowan, Tina M. ^{[4
]}

Ruggero, Davide ^{[2
,3
]}

Sweet-Cordero, E. Alejandro ^{[1
,5
,6
]}

机构：

[1] Stanford Univ, Sch Med, Dept Pediat, Div Hematol & Oncol, Stanford, CA 94305 USA

[2] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Sch Med, San Francisco, CA 94158 USA

[3] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, Dept Urol, San Francisco, CA 94158 USA

[4] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[5] Univ Calif San Francisco, Dept Pediat, Div Hematol & Oncol, San Francisco, CA 94158 USA

[6] Univ Calif San Francisco, Rock Hall Room 384D,1550 Fourth St, San Francisco, CA 94158 USA

来源：

CANCER CELL | 2018年 / 33卷 / 01期

关键词：

ACTIVATING TRANSCRIPTION FACTOR-4; CANCER-CELLS; PROTEIN-SYNTHESIS; OXIDATIVE STRESS; MAMMALIAN-CELLS; MESSENGER-RNA; BREAST-CANCER; LUNG-CANCER; ER-STRESS; GLUTAMINE;

D O I：

10.1016/j.ccell.2017.12.003

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

KRAS is a regulator of the nutrient stress response in non-small-cell lung cancer (NSCLC). Induction of the ATF4 pathway during nutrient depletion requires AKT and NRF2 downstream of KRAS. The tumor suppressor KEAP1 strongly influences the outcome of activation of this pathway during nutrient stress; loss of KEAP1 in KRAS mutant cells leads to apoptosis. Through ATF4 regulation, KRAS alters amino acid uptake and asparagine biosynthesis. The ATF4 target asparagine synthetase (ASNS) contributes to apoptotic suppression, protein biosynthesis, and mTORC1 activation. Inhibition of AKT suppressed ASNS expression and, combined with depletion of extracellular asparagine, decreased tumor growth. Therefore, KRAS is important for the cellular response to nutrient stress, and ASNS represents a promising therapeutic target in KRAS mutant NSCLC.

引用

页码：91 / +

页数：23

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