Berberine radiosensitizes human esophageal cancer cells by downregulating homologous recombination repair protein RAD51.
Berberine radiosensitizes human esophageal cancer cells by downregulating homologous recombination repair protein RAD51.
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小檗碱通过下调同源重组修复蛋白 RAD51 使人食管癌细胞放射增敏
DOI：
10.1371/journal.pone.0023427
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Shao C
中科院分区：
文献类型：
--
作者：
Liu Q;Jiang H;Liu Z;Wang Y;Zhao M;Hao C;Feng S;Guo H;Xu B;Yang Q;Gong Y;Shao C
食管鳞状细胞癌（ESCC）预后较差。虽然化疗和放疗的联合治疗可以提高生存率，但大多数患者会在五年内死亡。开发赋予癌细胞特异性化学和放射敏感性的药物可能会改善食管鳞癌的治疗。我们在这里报告了小檗碱作为食管鳞癌细胞的有效放射增敏剂的发现。低浓度（<15 µM）小檗碱显着使食管鳞癌细胞放射增敏。 X 射线诱导的 DNA 双链断裂 (DSB) 在经小檗碱预处理的 ESCC 细胞中持续时间更长。小檗碱预处理导致食管鳞癌细胞中同源重组修复的关键参与者 RAD51 显着下调，但在非恶性人类细胞中则不然。通过RNA干扰下调RAD51同样使癌细胞放射增敏，相反，引入外源RAD51能够显着抵消小檗碱的放射增敏作用，从而确立RAD51作为放射敏感性的关键决定因素。我们还观察到RAD51在人类ESCC组织中普遍过表达，这表明有必要下调RAD51以在临床上实现ESCC的高放疗或化疗疗效，因为已知RAD51的过表达会赋予放疗和化疗耐药性。小檗碱可有效下调RAD51，赋予食管癌细胞放射敏感性。其作为食管癌化疗和放疗辅助的临床应用值得探讨。
Esophageal squamous cell carcinomas (ESCC) have poor prognosis. While combined modality of chemotherapy and radiotherapy increases survival, most patients die within five years. Development of agents that confer cancer cell-specific chemo- and radiosensitivity may improve the therapy of ESCC. We here reported the discovery of berberine as a potent radiosensitizing agent on ESCC cells. Berberine at low concentrations (<15 µM) substantially radiosensitized ESCC cells. X-ray induced DNA double-strand breaks (DSBs) persist longer in ESCC cells pretreated with berberine. Berberine pretreatment led to a significant downregulation of RAD51, a key player in homologous recombination repair, in ESCC cells, but not in non-malignant human cells. Downregulation of RAD51 by RNA interference similarly radiosensitized the cancer cells, and, conversely, introduction of exogenous RAD51 was able to significantly counteract the radiosensitizing effect of berberine, thus establishing RAD51 as a key determinant in radiation sensitivity. We also observed that RAD51 was commonly overexpressed in human ESCC tissues, suggesting that it is necessary to downregulate RAD51 to achieve high radio- or chemotherapeutic efficacy of ESCC in clinic, because overexpression of RAD51 is known to confer radio- and chemoresistance. Berberine can effectively downregulate RAD51 in conferring radiosensitivity on esophageal cancer cells. Its clinical application as an adjuvant in chemotherapy and radiotherapy of esophageal cancers should be explored.
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DOI：
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