Abstract
<div>Abstract<p>This study aims to explore whether E545K, the most common hotspot mutation of <i>PIK3CA</i> in cervical cancer, confers radioresistance to cervical cancer cells, to demonstrate the underling mechanism, and to develop the effective targets. SiHa and MS751 cells with <i>PIK3CA</i>-WT and <i>PIK3CA</i>-E545K were established by lentiviral transfection. The radiosensitivity was assessed by colony formation, cell cycle, cell apoptosis, DNA damage, and repair assay. The growth and immunohistochemical assay of xenograft tumor–related toxicity were evaluated <i>in vivo</i>. It was indicated that more cells with <i>PIK3CA</i>-E545K arrested in S phase. Irradiation (IR) led to more survival percentage, less apoptosis, fewer pH2A.X foci, and higher expression of Chk1/2 in SiHa and MS751 cells bearing <i>PIK3CA</i>-E545K. Mechanically, AKT/GSK3β/β-catenin pathway was highly activated, and more β-catenin was found accumulated in nucleus in cells with <i>PIK3CA</i>-E545K after IR. Furthermore, targeting β-catenin by shRNA or XAV939 enhanced IR sensitivity in cells with <i>PIK3CA</i>-WT and <i>PIK3CA</i>-E545K, whereas it was more notably in the latter. β-Catenin shRNA and XAV939 increased IR-mediated inhibition of colony formation with highly activated p53/bcl2/bax pathway. XAV939 enhanced IR-caused apoptosis, DNA damage, overcame S-phase arrest, DNA repair and reversed β-catenin nuclear accumulation in MS751 cells with <i>PIK3CA</i>-E545K. <i>In vivo</i>, XAV939 enhanced the radiosensitivity of cervical cancer xenografts with <i>PIK3CA</i>-E545K with invisible viscera toxicity. The findings demonstrate that cervical cancer cells with <i>PIK3CA</i>-E545K are resistant to IR by enhancing the expression and nuclear accumulation of β-catenin. Targeting β-catenin reverses the radioresistance, which suggests possible areas for preclinical research on β-catenin inhibition for strengthening the radiosensitivity of cervical cancer.</p></div>
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