title: Cysteine transporter SLC3A1 promotes breast cancer tumorigenesis.
abstract: 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.
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine; Institute of Cancer Stem Cell, Dalian Medical University.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine.
authors.forename: Yongbin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1st affiliated hospital of Soochow University.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Lv
authors.affiliation: NIEHS, National Institute of Health.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine.
authors.forename: Jun
authors.initials: J
authors.lastname: Mi
mesh_terms: D026923:Amino Acid Transport Systems, Basic / Q000235:genetics / Q000378:metabolism*; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000503:physiopathology*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016019:Survival Analysis
chemical_list: D026923:Amino Acid Transport Systems, Basic; D026921:Amino Acid Transport Systems, Neutral; C489857:SLC3A1 protein, human; D003545:Cysteine
keywords: PDK1; ROS; breast cancer; cysteine; solute carrier SLC3A1