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

被引:195
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
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
收藏
页码:354 / 369
页数:16
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