Abstract
Abstract Tumor cells have an altered metabolism that distinguishes it from their normal counterpart. Intriguingly, tumor cells show increased use of glutamine to fuel catabolic processes. Therefore, altered metabolic tumors have been considered as a good target for anticancer therapy. Ring finger protein 5 (RNF5) is an ER membrane-associated ubiquitin E3 ligase. RNF5 expression has been associated with breast cancer progression. We identified solute carrier family 1 member 5 (SLC1A5) as a possible RNF5 regulated protein using a MS analysis of breast cancer cells. SLC1A5 is a high affinity L-glutamine transporter, which is highly expressed in tumors such as breast, liver and lung. RNF5 promotes ubiquitination-mediated degradation of SLC1A5 in response to chemotherapeutic drugs known to induce ER stress. RNF5-mediated SLC1A5 instability attenuated mTOR signaling, leading to inhibition of tumor cell proliferation and promotion of apoptosis/autophagy. The loss of RNF5 in PyMT-MMTV crossed with RNF5 mutant animals developed less differentiated mammary tumors, which exhibit increased levels of SLC1A5. TMA analysis of human breast cancer tumors identified a fraction that exhibited an inverse correlation between RNF5 and SLC1A5 expression. Notably, reduced expression of SLC1A5 exhibited a strong association with improved prognosis of breast cancer. Taken together, our observations identify mechanisms underlying the control of SLC1A5 stability, and the implications of such regulation for mTOR signaling and breast cancer survival in response to therapy. Citation Format: Young Joo Jeon, Sihem Khelifa, Yongmei Feng, Eric Lau, Robert Cardiff, Hyungsoo Kim, David L. Rimm, Yuval Kluger, Ze'ev Ronai. RNF5 mediates ER stress-induced degradation of SLC1A5 in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2440. doi:10.1158/1538-7445.AM2014-2440
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