title: Nrf2- and ATF4-dependent upregulation of xCT modulates the sensitivity of T24 bladder carcinoma cells to proteasome inhibition.
abstract: The ubiquitin-proteasome pathway degrades ubiquitinated proteins to remove damaged or misfolded protein and thus plays an important role in the maintenance of many important cellular processes. Because the pathway is also crucial for tumor cell growth and survival, proteasome inhibition by specific inhibitors exhibits potent antitumor effects in many cancer cells. xCT, a subunit of the cystine antiporter system xc (-), plays an important role in cellular cysteine and glutathione homeostasis. Several recent reports have revealed that xCT is involved in cancer cell survival; however, it was unknown whether xCT affects the cytotoxic effects of proteasome inhibitors. In this study, we found that two stress-inducible transcription factors, Nrf2 and ATF4, were upregulated by proteasome inhibition and cooperatively enhance human xCT gene expression upon proteasome inhibition. In addition, we demonstrated that the knockdown of xCT by small interfering RNA (siRNA) or pharmacological inhibition of xCT by sulfasalazine (SASP) or (S)-4-carboxyphenylglycine (CPG) significantly increased the sensitivity of T24 cells to proteasome inhibition. These results suggest that the simultaneous inhibition of both the proteasome and xCT could have therapeutic benefits in the treatment of bladder tumors.
authors.affiliation: Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Peng
authors.initials: P
authors.lastname: Ye
authors.affiliation: Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan jmimura@cc.hirosaki-u.ac.jp.
authors.forename: Junsei
authors.initials: J
authors.lastname: Mimura
authors.affiliation: Department of Food and Applied Life Sciences, Faculty of Agriculture, Yamagata University, Tsuruoka, Yamagata, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Okada
authors.affiliation: Department of Food and Applied Life Sciences, Faculty of Agriculture, Yamagata University, Tsuruoka, Yamagata, Japan.
authors.forename: Hideyo
authors.initials: H
authors.lastname: Sato
authors.affiliation: Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Maruyama
authors.affiliation: Department of Urology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Chikara
authors.initials: C
authors.lastname: Ohyama
authors.affiliation: Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D012460:Sulfasalazine / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: C497109:ATF4 protein, human; D027182:Amino Acid Transport System y+; D000970:Antineoplastic Agents; D001897:Boronic Acids; D007976:Leupeptins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009842:Oligopeptides; D011719:Pyrazines; D034741:RNA, Small Interfering; C118895:SLC7A11 protein, human; C453101:carboxyphenylglycine; D051701:Activating Transcription Factor 4; D012460:Sulfasalazine; D000069286:Bortezomib; C524865:carfilzomib; D046988:Proteasome Endopeptidase Complex; D005978:Glutathione; D003545:Cysteine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D005998:Glycine; C078846:epoxomicin