Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies.
Research paper by
Young Joo YJ Jeon, Sihem S Khelifa, Boris B Ratnikov, David A DA Scott, Yongmei Y Feng, Fabio F Parisi, Chelsea C Ruller, Eric E Lau, Hyungsoo H Kim, Laurence M LM Brill, Tingting T Jiang, David L DL Rimm, Robert D RD Cardiff, Gordon B GB Mills, Jeffrey W JW Smith, Andrei L AL Osterman, Yuval Y Kluger, Ze'ev A ZA Ronai
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.