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Regulation of Glutamine Carrier Proteins by RNF5 Determines Breast Cancer Response to ER Stress-Inducing Chemotherapies
- Jeon, Young Joo;
- Khelifa, Sihem;
- Ratnikov, Boris;
- Scott, David A;
- Feng, Yongmei;
- Parisi, Fabio;
- Ruller, Chelsea;
- Lau, Eric;
- Kim, Hyungsoo;
- Brill, Laurence M;
- Jiang, Tingting;
- Rimm, David L;
- Cardiff, Robert D;
- Mills, Gordon B;
- Smith, Jeffrey W;
- Osterman, Andrei L;
- Kluger, Yuval;
- Ronai, Ze’ev A
- et al.
Published Web Location
https://doi.org/10.1016/j.ccell.2015.02.006Abstract
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.
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