p22phox confers resistance to cisplatin, by blocking its entry into the nucleus
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Chih-Chang Hung1,2,*, Chen-Yu Chien3,4,5,*, Wei-Fan Chiang6,7, Chang-Shen Lin1, Tzyh-Chyuan Hour8, Hau-Ren Chen9, Ling-Feng Wang3,10, Jenq-Yuh Ko11, Chi-Hua Chang12, Jeff Yi-Fu Chen2
1Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
2Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan
3Department of Otorhinolaryngology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
4Department of Otorhinolaryngology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
5Department of Otorhinolaryngology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
6Department of Dentistry, Chi-Mei Medical Center, Liouying, Taiwan
7Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
8Department of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan
9Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chia-Yi, Taiwan
10Department of Otorhinolaryngology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
11Department of Otolaryngology, National Taiwan University, College of Medicine, Taipei, Taiwan
12Department of Dentistry, Chang Gung Memorial Hospital, Kaohsiung, Taiwan
*These authors have contributed equally to this work
Jeff Yi-Fu Chen, e-mail: [email protected]
Keywords: p22phox, CDDP resistance, apoptosis, PI3K/Akt, oral squamous cell carcinoma (OSCC)
Received: September 30, 2014 Accepted: December 11, 2014 Published: February 19, 2015
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.
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