کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2107040 | 1083650 | 2015 | 16 صفحه PDF | دانلود رایگان |
• Gln carrier proteins SLC1A5 and SLC38A2 are regulated by ubiquitin ligase RNF5
• Glutamine uptake and mTOR activity following ERS is RNF5-SLC1A5 dependent
• RNF5 inhibition of SLC1A5 is required for paclitaxel-induced apoptosis of BCa cells
• Low SLC1A5 expression in BCa TMA and RPPA associates with good prognosis
SummaryMany 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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Journal: - Volume 27, Issue 3, 9 March 2015, Pages 354–369