Abstract:
:This study aims to explore whether E545K, the most common hotspot mutation of PIK3CA 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 PIK3CA-WT and PIK3CA-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 in vivo It was indicated that more cells with PIK3CA-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 PIK3CA-E545K. Mechanically, AKT/GSK3β/β-catenin pathway was highly activated, and more β-catenin was found accumulated in nucleus in cells with PIK3CA-E545K after IR. Furthermore, targeting β-catenin by shRNA or XAV939 enhanced IR sensitivity in cells with PIK3CA-WT and PIK3CA-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 PIK3CA-E545K. In vivo, XAV939 enhanced the radiosensitivity of cervical cancer xenografts with PIK3CA-E545K with invisible viscera toxicity. The findings demonstrate that cervical cancer cells with PIK3CA-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.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Jiang W,Wu Y,He T,Zhu H,Ke G,Xiang L,Yang Hdoi
10.1158/1535-7163.MCT-19-0309subject
Has Abstractpub_date
2020-02-01 00:00:00pages
337-347issue
2eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-19-0309journal_volume
19pub_type
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0650
更新日期:2015-03-01 00:00:00
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pub_type: 杂志文章
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更新日期:2014-06-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0562
更新日期:2008-12-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-09-0966
更新日期:2010-09-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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更新日期:2003-01-01 00:00:00
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doi:10.1158/1535-7163.MCT-20-0130
更新日期:2021-01-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
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更新日期:2019-03-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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更新日期:2007-02-01 00:00:00
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pub_type: 杂志文章
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更新日期:2007-12-01 00:00:00