p22phox confers resistance to cisplatin, by blocking its entry into the nucleus
Journal
Oncotarget
Journal Volume
6
Journal Issue
6
Pages
4110-4125
Date Issued
2015
Author(s)
Hung C.-C
Chien C.-Y
Chiang W.-F
Lin C.-S
Hour T.-C
Chen H.-R
Wang L.-F
Chang C.-H
Chen J.Y.-F.
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.
Subjects
Apoptosis; CDDP resistance; Oral squamous cell carcinoma (OSCC); p22phox; PI3K/Akt
SDGs
Other Subjects
checkpoint kinase 1; cisplatin; protein kinase B; protein p22phox; protein p53; regulator protein; unclassified drug; antineoplastic agent; cisplatin; CYBA protein, human; reduced nicotinamide adenine dinucleotide phosphate oxidase; adult; apoptosis; Article; cell nucleus; cell protection; cellular distribution; clinical article; controlled study; cytoplasm; drug resistance; drug sensitivity; human; human cell; human tissue; IC50; middle aged; mouth squamous cell carcinoma; oral cancer cell line; protein expression; protein phosphorylation; signal transduction; upregulation; biosynthesis; Carcinoma, Squamous Cell; cell nucleus; drug resistance; female; gene silencing; genetics; Head and Neck Neoplasms; male; metabolism; Mouth Neoplasms; pathology; tumor cell line; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Nucleus; Cisplatin; Drug Resistance, Neoplasm; Female; Gene Knockdown Techniques; Head and Neck Neoplasms; Humans; Male; Middle Aged; Mouth Neoplasms; NADPH Oxidase; Up-Regulation
Publisher
Impact Journals LLC
Type
journal article