Jeon Young Joo, Khelifa Sihem, Ratnikov Boris, Scott David A, Feng Yongmei, Parisi Fabio, Ruller Chelsea, Lau Eric, Kim Hyungsoo, Brill Laurence M, Jiang Tingting, Rimm David L, Cardiff Robert D, Mills Gordon B, Smith Jeffrey W, Osterman Andrei L, Kluger Yuval, Ronai Ze'ev A
Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Department of Pathology, Yale University, New Haven, CT 06510, USA.
Cancer Cell. 2015 Mar 9;27(3):354-69. doi: 10.1016/j.ccell.2015.02.006.
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.
许多肿瘤细胞由代谢改变和对谷氨酰胺（Gln）的依赖性增加所驱动。我们发现泛素连接酶RNF5对L-谷氨酰胺载体蛋白SLC1A5和SLC38A2（SLC1A5/38A2）具有调控作用。紫杉醇诱导的乳腺癌（BCa）细胞内质网应激促进RNF5与SLC1A5/38A2的结合、泛素化及降解。这会减少Gln摄取、三羧酸循环成分水平、mTOR信号传导及细胞增殖，同时增加自噬和细胞死亡。Rnf5基因缺失的MMTV-PyMT乳腺肿瘤分化程度较低，且SLC1A5表达升高。而MDA-MB-231细胞中RNF5缺失会促进肿瘤发生并消除紫杉醇反应性，SLC1A5/38A2基因敲低则产生相反效果。BCa中RNF5（高）/SLC1A5/38A2（低）的反向表达与良好预后相关。因此，RNF5对Gln摄取的调控是BCa对化疗反应的基础。
