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

Young Joo Jeon, Sihem Khelifa, Boris Ratnikov, David A. Scott, Yongmei Feng, Fabio Parisi, Chelsea Ruller, Eric Lau, Hyungsoo Kim, Laurence M. Brill, Tingting Jiang, David L. Rimm, Robert D. Cardiff, Gordon B. Mills, Jeffrey W. Smith, Andrei L. Osterman, Yuval Kluger, Ze'ev A. Ronai

    Research output: Contribution to journalArticle

    81 Scopus citations

    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 RNF5hi/SLC1A5/38A2lo expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies.

    Original languageEnglish (US)
    Pages (from-to)354-369
    Number of pages16
    JournalCancer Cell
    Volume27
    Issue number3
    DOIs
    StatePublished - Mar 9 2015

    ASJC Scopus subject areas

    • Oncology
    • Cell Biology
    • Cancer Research

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  • Cite this

    Jeon, Y. J., Khelifa, S., Ratnikov, B., Scott, D. A., Feng, Y., Parisi, F., Ruller, C., Lau, E., Kim, H., Brill, L. M., Jiang, T., Rimm, D. L., Cardiff, R. D., Mills, G. B., Smith, J. W., Osterman, A. L., Kluger, Y., & Ronai, Z. A. (2015). Regulation of Glutamine Carrier Proteins by RNF5 Determines Breast Cancer Response to ER Stress-Inducing Chemotherapies. Cancer Cell, 27(3), 354-369. https://doi.org/10.1016/j.ccell.2015.02.006