title: p22phox confers resistance to cisplatin, by blocking its entry into the nucleus.
abstract: Cisplatin (CDDP) is a potent chemotherapeutic agent but resistance to the drug remains a major challenge in cancer treatment. To evaluate the efficacy of CDDP in oral squamous cell carcinoma (OSCC), we found that p22phox was highly expressed in CDDP-resistant OSCC specimens. Knockdown of p22phox sensitized OSCC cell lines to CDDP (P < 0.05). Stable overexpression of p22phox augmented CDDP resistance, as evidenced by the significantly higher IC50 values. This cytoprotective effect was attributed to the abrogation of CDDP-induced apoptosis. Akt phosphorylation was increased in p22phox stable lines. However, blocking PI3K/Akt pathway only partially restored CDDP-induced apoptosis. In addition, the overexpressed p22phox in OSCC cells exhibited cytoplasmic localization with enhanced perinuclear expression, consistent with the localization pattern in OSCC specimens. Remarkably, CDDP entry into the nucleus was severely impaired in p22phox-overexpressing cells (P < 0.001), and cytoplasmically accumulated CDDP was co-localized with overexpressed p22phox. This was supported by decreased CDDP-DNA adduct formation and delayed chk1-p53 signaling activation. Together, overexpression of p22phox sequestered CDDP and caused defective CDDP entry into the nucleus, significantly attenuating CDDP-induced apoptosis. Such diminished apoptosis was further abolished by p22phox-activating PI3K/Akt pathway. Our work has suggested a novel biomarker and insight into the mechanism of CDDP resistance.
authors: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Chih-Chang
authors: CC
authors: Hung
authors: Department of Otorhinolaryngology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Otorhinolaryngology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|Department of Otorhinolaryngology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Chen-Yu
authors: CY
authors: Chien
authors: Department of Dentistry, Chi-Mei Medical Center, Liouying, Taiwan.|Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.
authors: Wei-Fan
authors: WF
authors: Chiang
authors: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Chang-Shen
authors: CS
authors: Lin
authors: Department of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Tzyh-Chyuan
authors: TC
authors: Hour
authors: Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan.
authors: Hau-Ren
authors: HR
authors: Chen
authors: Department of Otorhinolaryngology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Otorhinolaryngology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Ling-Feng
authors: LF
authors: Wang
authors: Department of Otolaryngology, National Taiwan University, College of Medicine, Taipei, Taiwan.
authors: Jenq-Yuh
authors: JY
authors: Ko
authors: Department of Dentistry, Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors: Chi-Hua
authors: CH
authors: Chang
authors: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Jeff Yi-Fu
authors: JY
authors: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D055785:Gene Knockdown Techniques; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000077195:Squamous Cell Carcinoma of Head and Neck; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D019255:NADPH Oxidases; C086986:CYBA protein, human; D002945:Cisplatin