Theranostics 2017; 7(4):1036-1046. doi:10.7150/thno.18005
Cysteine transporter SLC3A1 promotes breast cancer tumorigenesis
1. Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine
280 South Choongqing Rd., Shanghai 200025, China
2. Institute of Cancer Stem Cell, Dalian Medical University
9. West South-Lvshun Rd., Dalian, Liaoning 116044, China
3. 1st affiliated hospital of Soochow University
188 Shizi Rd. Suzhou, Jiangsu 215006, China
4. NIEHS, National Institute of Health
111 T W Alexander Dr., Rall Building, Research Triangle Prk, NC 27709, USA.
* These authors contribute equally to this study.
Cysteine is an essential amino acid for infants, aged people as well as patients with metabolic disorders. Although the thiol group of cysteine side chain is active in oxidative reactions, the role of cysteine in cancer remains largely unknown. Here, we report that the expression level of the solute carrier family 3, member 1 (SLC3A1), the cysteine carrier, tightly correlated with clinical stages and patients' survival. Elevated SLC3A1 expression accelerated the cysteine uptake and the accumulation of reductive glutathione (GSH), leading to reduced reactive oxygen species (ROS). ROS increased the stability and activity of PP2Ac, resulting in decreased AKT activity. Hence, SLC3A1 activated the AKT signaling through inhibiting PP2A phosphatase activity. Consistently, overexpression of SLC3A1 enhanced tumorigenesis of breast cancer cells, whereas blocking SLC3A1 either with specific siRNA or SLC3A1 specific inhibitor sulfasalazine suppressed tumor growth and also abolished dietary NAC-promoted tumor growth. Collectively, our data demonstrate that SLC3A1 promotes cysteine uptake and determines cellular response to antioxidant N-acetylcysteine, suggesting SLC3A1 is a potential therapeutic target for breast cancer.
Keywords: solute carrier SLC3A1, breast cancer, ROS, cysteine, PDK1
Jiang Y, Cao Y, Wang Y, Li W, Liu X, Lv Y, Li X, Mi J. Cysteine transporter SLC3A1 promotes breast cancer tumorigenesis. Theranostics 2017; 7(4):1036-1046. doi:10.7150/thno.18005. Available from http://www.thno.org/v07p1036.htm