title: Cystine-glutamate transporter SLC7A11 in cancer chemosensitivity and chemoresistance.
abstract: SLC7A11 (xCT), together with SLC3A2 (4F2hc), encodes the heterodimeric amino acid transport system x(c)-, which mediates cystine-glutamate exchange and thereby regulates intracellular glutathione levels. We used microarrays to analyze gene expression of transporters in 60 human cancer cell lines used by the National Cancer Institute for drug screening (NCI-60). The expression of SLC7A11 showed significant correlation with that of SLC3A2 (r = 0.66), which in turn correlated with SLC7A5 (r = 0.68), another known partner for SLC3A2, and with T1A-2 (r = 0.60; all P < 0.0001). Linking expression of SLC7A11 with potency of 1,400 candidate anticancer drugs identified 39 showing positive correlations, e.g., amino acid analogue, L-alanosine, and 296 with negative correlations, e.g., geldanamycin. However, no significant correlation was observed with the geldanamycin analogue 17-allylamino, 17-demethoxygeldanamycin (17-AAG). Inhibition of transport system x(c)- with glutamate or (S)-4-carboxyphenylglycine in lung A549 and HOP-62, and ovarian SK-OV-3 cells, reduced the potency of L-alanosine and lowered intracellular glutathione levels. This further resulted in increased potency of geldanamycin, with no effect on 17-AAG. Down-regulation of SLC7A11 by small interfering RNA affected drug potencies similarly to transport inhibitors. The inhibitor of gamma-glutamylcysteine synthetase, buthionine sulfoximine, also decreased intracellular glutathione levels and enhanced potency of geldanamycin, but did not affect L-alanosine. These results indicate that SLC7A11 mediates cellular uptake of L-alanosine but confers resistance to geldanamycin by supplying cystine for glutathione maintenance. SLC7A11 expression could serve as a predictor of cellular response to L-alanosine and glutathione-mediated resistance to geldanamycin, yielding a potential target for increasing chemosensitivity to multiple drugs.
authors.affiliation: Program of Pharmacogenomics, Department of Pharmacology, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210-1239, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Zunyan
authors.initials: Z
authors.lastname: Dai
authors.forename: Catalin
authors.initials: C
authors.lastname: Barbacioru
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadée
mesh_terms: D027182:Amino Acid Transport System y+ / Q000096:biosynthesis / Q000235:genetics*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D003553:Cystine / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D027182:Amino Acid Transport System y+; D000964:Antimetabolites, Antineoplastic; D034741:RNA, Small Interfering; C118895:SLC7A11 protein, human; D003553:Cystine; D019328:Buthionine Sulfoximine; D005978:Glutathione