Department of Urology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, PR China.
Oncol Rep. 2012 Dec;28(6):2247-54. doi: 10.3892/or.2012.2068. Epub 2012 Oct 1.
Radioresistance is responsible for treatment failure after radiotherapy in localized prostate cancer, while prostate cancer stem cells promote radioresistance by preferential activation of the DNA damage response. Chk1 inhibition has been shown to sensitize many tumor cells to radiation. However, whether Chk1 inhibition can potentiate the cytotoxic effects of radiation on prostate cancer stem cells remains to be elucidated. In this study, CD133+CD44+ cells were isolated using microbeads and were found to possess cancer stem cell properties. Using shRNA, Chk1 was knocked down in the sorted CD133+CD44+ cells. Our results demonstrated that Chk1 knockdown abrogated the radiation-induced G2/M arrest, inhibited DNA damage repair and promoted premature mitosis, leading to increased apoptosis in the radiated sorted CD133+CD44+ cells. Moreover, these effects were accompanied by caspase-2 activation and the inactivation of phosphorylated Cdc25C and Cdc2. Our results suggest that Chk1 knockdown increases the radiosensitivity of CD133+CD44+ prostate cancer stem cells. Chk1 knockdown in prostate cancer stem cells may be an effective therapeutic strategy against prostate cancer.
放射抵抗是导致局部前列腺癌放射治疗失败的原因，而前列腺癌干细胞通过优先激活 DNA 损伤反应促进放射抵抗。已经表明 Chk1 抑制可以使许多肿瘤细胞对辐射敏感。然而，Chk1 抑制是否可以增强辐射对前列腺癌干细胞的细胞毒性作用仍有待阐明。在这项研究中，使用微珠分离出 CD133+CD44+细胞，并发现它们具有癌症干细胞特性。使用 shRNA 敲低分选的 CD133+CD44+细胞中的 Chk1。我们的结果表明，Chk1 敲低消除了辐射诱导的 G2/M 期阻滞，抑制了 DNA 损伤修复，并促进了过早有丝分裂，导致辐射分选的 CD133+CD44+细胞中凋亡增加。此外，这些效应伴随着半胱天冬酶-2 的激活和磷酸化 Cdc25C 和 Cdc2 的失活。我们的结果表明，Chk1 敲低增加了 CD133+CD44+前列腺癌干细胞的放射敏感性。Chk1 敲低在前列腺癌干细胞中可能是一种有效的治疗前列腺癌的策略。
