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

YJ Jeon, S Khelifa, B Ratnikov, DA Scott, Y Feng… - Cancer cell, 2015 - cell.com
YJ Jeon, S Khelifa, B Ratnikov, DA Scott, Y Feng, F Parisi, C Ruller, E Lau, H Kim, LM Brill…
Cancer cell, 2015cell.com
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 …
Summary
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.
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