title: IGF-I regulates redox status in breast cancer cells by activating the amino acid transport molecule xC-.
abstract: Insulin-like growth factors (IGF) stimulate cell growth in part by increasing amino acid uptake. xCT (SLC7A11) encodes the functional subunit of the cell surface transport system xC(-), which mediates cystine uptake, a pivotal step in glutathione synthesis and cellular redox control. In this study, we show that IGF-I regulates cystine uptake and cellular redox status by activating the expression and function of xCT in estrogen receptor-positive (ER(+)) breast cancer cells by a mechanism that relies on the IGF receptor substrate-1 (IRS-1). Breast cancer cell proliferation mediated by IGF-I was suppressed by attenuating xCT expression or blocking xCT activity with the pharmacologic inhibitor sulfasalazine (SASP). Notably, SASP sensitized breast cancer cells to inhibitors of the type I IGF receptor (IGF-IR) in a manner reversed by the reactive oxygen species (ROS) scavenger N-acetyl-L-cysteine. Thus, IGF-I promoted the proliferation of ER(+) breast cancer cells by regulating xC(-) transporter function to protect cancer cells from ROS in an IRS-1-dependent manner. Our findings suggest that inhibiting xC(-) transporter function may synergize with modalities that target the IGF-IR to heighten their therapeutic effects.
authors.affiliation: Authors' Affiliations: Masonic Cancer Center; and Departments of Pharmacology and Medicine, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Yuzhe
authors.initials: Y
authors.lastname: Yang
authors.forename: Douglas
authors.initials: D
authors.lastname: Yee
mesh_terms: D027182:Amino Acid Transport System y+ / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D003553:Cystine / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism* / Q000494:pharmacology; D061986:MCF-7 Cells; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D027182:Amino Acid Transport System y+; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; C118895:SLC7A11 protein, human; D003553:Cystine; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D005978:Glutathione