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Cancer Cell. 2015 Mar 9;27(3):354-69. doi: 10.1016/j.ccell.2015.02.006.

Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies.

Author information

1
Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
2
Department of Pathology, Yale University, New Haven, CT 06510, USA.
3
Department of Pathology, University of California, Davis, Davis, CA 95616, USA.
4
Department of Systems Biology, MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. Electronic address: ronai@sbmri.org.

Abstract

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.

PMID:
25759021
PMCID:
PMC4356903
DOI:
10.1016/j.ccell.2015.02.006
[Indexed for MEDLINE]
Free PMC Article

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