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p22phox confers resistance to cisplatin, by blocking its entry into the nucleus.

Hung CC, Chien CY, Chiang WF, Lin CS, Hour TC, Chen HR, Wang LF, Ko JY, Chang CH, Chen JY - Oncotarget (2015)

Bottom Line: This cytoprotective effect was attributed to the abrogation of CDDP-induced apoptosis.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.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

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.

No MeSH data available.


Related in: MedlinePlus

Dual modes of action of p22phox in the mechanism of CDDP resistanceIn OSCC cells, despite regular CDDP uptake into the cells, overexpression of p22phox possibly sequesters CDDP in the cytoplasm, resulting in diminished CDDP entry to and DNA adducts formation in the nucleus. The decreased DNA damage triggers attenuated apoptotic signaling that is further inhibited by p22phox-activating PI3K/Akt signaling pathway.
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Figure 8: Dual modes of action of p22phox in the mechanism of CDDP resistanceIn OSCC cells, despite regular CDDP uptake into the cells, overexpression of p22phox possibly sequesters CDDP in the cytoplasm, resulting in diminished CDDP entry to and DNA adducts formation in the nucleus. The decreased DNA damage triggers attenuated apoptotic signaling that is further inhibited by p22phox-activating PI3K/Akt signaling pathway.

Mentions: In conclusion, this study demonstrates for the first time that p22phox, a crucial component for NADPH oxidase activation, modulates CDDP resistance in OSCC cells. We found that p22phox was highly expressed in CDDP-resistant carcinoma tissues in oral cancer patients. In vitro studies demonstrated that overexpression of p22phox abrogated CDDP-induced apoptosis, thereby conferring cytoprotective effect against CDDP in OSCC cells. There were increased levels of basal Akt activity in p22phox stable lines, which only partially accounted for p22phox-dependent inhibition of CDDP-induced apoptosis. Furthermore, fluorescence-labeled CDDP was accumulated and co-localized with the overexpressed p22phox in the cytoplasm, which was supported by the reduced CDDP-adduct formation and chk1-p53 activation. Collectively, despite normal CDDP uptake into the cells, the entry of CDDP into the nucleus was severely impaired presumably due to sequestration by p22phox in the cytoplasm, eliciting a series of downstream effects including decreased DNA adduct formation and weakened apoptotic signaling. Finally the attenuated apoptosis was further inhibited by p22phox-activating PI3K/Akt pathway, thereby leading to CDDP resistance in OSCC cells (Figure 8). These data have provided a novel biomarker and insight into the mechanism of chemoresistance in oral cancer.


p22phox confers resistance to cisplatin, by blocking its entry into the nucleus.

Hung CC, Chien CY, Chiang WF, Lin CS, Hour TC, Chen HR, Wang LF, Ko JY, Chang CH, Chen JY - Oncotarget (2015)

Dual modes of action of p22phox in the mechanism of CDDP resistanceIn OSCC cells, despite regular CDDP uptake into the cells, overexpression of p22phox possibly sequesters CDDP in the cytoplasm, resulting in diminished CDDP entry to and DNA adducts formation in the nucleus. The decreased DNA damage triggers attenuated apoptotic signaling that is further inhibited by p22phox-activating PI3K/Akt signaling pathway.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4414176&req=5

Figure 8: Dual modes of action of p22phox in the mechanism of CDDP resistanceIn OSCC cells, despite regular CDDP uptake into the cells, overexpression of p22phox possibly sequesters CDDP in the cytoplasm, resulting in diminished CDDP entry to and DNA adducts formation in the nucleus. The decreased DNA damage triggers attenuated apoptotic signaling that is further inhibited by p22phox-activating PI3K/Akt signaling pathway.
Mentions: In conclusion, this study demonstrates for the first time that p22phox, a crucial component for NADPH oxidase activation, modulates CDDP resistance in OSCC cells. We found that p22phox was highly expressed in CDDP-resistant carcinoma tissues in oral cancer patients. In vitro studies demonstrated that overexpression of p22phox abrogated CDDP-induced apoptosis, thereby conferring cytoprotective effect against CDDP in OSCC cells. There were increased levels of basal Akt activity in p22phox stable lines, which only partially accounted for p22phox-dependent inhibition of CDDP-induced apoptosis. Furthermore, fluorescence-labeled CDDP was accumulated and co-localized with the overexpressed p22phox in the cytoplasm, which was supported by the reduced CDDP-adduct formation and chk1-p53 activation. Collectively, despite normal CDDP uptake into the cells, the entry of CDDP into the nucleus was severely impaired presumably due to sequestration by p22phox in the cytoplasm, eliciting a series of downstream effects including decreased DNA adduct formation and weakened apoptotic signaling. Finally the attenuated apoptosis was further inhibited by p22phox-activating PI3K/Akt pathway, thereby leading to CDDP resistance in OSCC cells (Figure 8). These data have provided a novel biomarker and insight into the mechanism of chemoresistance in oral cancer.

Bottom Line: This cytoprotective effect was attributed to the abrogation of CDDP-induced apoptosis.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.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

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.

No MeSH data available.


Related in: MedlinePlus