Regulation of Glutamine Carrier Proteins by RNF5 Determines Breast Cancer Response to ER Stress-Inducing Chemotherapies

被引：198

作者：

Jeon, Young Joo ^{[1
]}

Khelifa, Sihem ^{[2
]}

Ratnikov, Boris ^{[1
]}

Scott, David A. ^{[1
]}

Feng, Yongmei ^{[1
]}

Parisi, Fabio ^{[2
]}

Ruller, Chelsea ^{[1
]}

Lau, Eric ^{[1
]}

Kim, Hyungsoo ^{[1
]}

Brill, Laurence M. ^{[1
]}

Jiang, Tingting ^{[2
]}

Rimm, David L. ^{[2
]}

Cardiff, Robert D. ^{[3
]}

Mills, Gordon B. ^{[4
]}

Smith, Jeffrey W. ^{[1
]}

Osterman, Andrei L. ^{[1
]}

Kluger, Yuval ^{[2
]}

Ronai, Ze'ev A. ^{[1
]}

机构：

[1] Sanford Burnham Med Res Inst, Tumor Initiat & Maintenance Program, Ctr Canc, La Jolla, CA 92037 USA

[2] Yale Univ, Dept Pathol, New Haven, CT 06510 USA

[3] Univ Calif Davis, Dept Pathol, Davis, CA 95616 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

来源：

CANCER CELL | 2015年 / 27卷 / 03期

关键词：

ENDOPLASMIC-RETICULUM STRESS; AMINO-ACID TRANSPORTER; C-MYC; AUTOPHAGY; SURVIVAL; PATHWAY; CELLS; METABOLISM; APOPTOSIS; EXPRESSION;

D O I：

10.1016/j.ccell.2015.02.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. This decreases Gln uptake, levels of TCA cycle components, mTOR signaling, and proliferation while increasing autophagy and cell death. Rnf5-deficient MMTV-PyMT mammary tumors were less differentiated and showed elevated SLC1A5 expression. Whereas RNF5 depletion in MDA-MB-231 cells promoted tumorigenesis and abolished paclitaxel responsiveness, SLC1A5/38A2 knockdown elicited opposing effects. Inverse RNF5(hi)/SLC1A5/38A2(lo) expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies.

引用

页码：354 / 369

页数：16

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