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首页> 外文期刊>Cancer biology & therapy >Knockdown of Chk1 sensitizes human colon carcinoma HCT116 cells in a p53-dependent manner to lidamycin through abrogation of a G2/M checkpoint and induction of apoptosis.
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Knockdown of Chk1 sensitizes human colon carcinoma HCT116 cells in a p53-dependent manner to lidamycin through abrogation of a G2/M checkpoint and induction of apoptosis.

机译：通过取消G2 / M检查点和诱导凋亡，Chk1的敲低以p53依赖性方式使人结肠癌HCT116细胞对利达霉素敏感。

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摘要

Recent advances in cell cycle regulation have led to a suggestion of therapeutically targeting cell cycle checkpoint pathways in cancer cells to increase the toxicity of DNA-damaging agents. In this study, we investigate whether knockdowns of checkpoint kinases Chk1 and Chk2 by RNA interfering potentiate the cytotoxicity and abrogate G(2)/M checkpoint induced by DNA-damaging agent lidamycin (LDM) in HCT116 cells with different p53 status. Our results showed that Chk1 knockdown enhanced the cytotoxicity of LDM through abrogating G(2)/M arrest and increasing apoptosis to a greater extent in HCT116 p53(-/-) cells than in p53(wt) cells. Abrogation of LDM-induced G(2)/M arrest by Chk1 knockdown was associated with reducing the inactivated phosphorylations of Cdc25C and Cdc2. LDM-induced gamma-H2AX was increased in cells with Chk1 knockdown, indicating that DNA double-strand breaks (DSBs) were enhanced. Furthermore, knockdown of Chk1 also increased LDM-mediated apoptotic cell death in p53 knockout cells with activation of caspase-2 and caspase-3. On the contrary, knockdown of Chk2 had no impact on G(2)/M arrest or apoptosis induced by LDM. Moreover, dual knockdown of Chk1 and Chk2 failed to achieve better efficacy than Chk1 alone. Taken together, we suggest that Chk1 is a potential therapeutic target to sensitize human p53 deficient cancer cells to LDM.
机译：细胞周期调节的最新进展已导致建议治疗性靶向癌细胞中的细胞周期检查点途径，以增加DNA损伤剂的毒性。在这项研究中，我们调查是否通过RNA干扰检查点激酶Chk1和Chk2的敲低增强了细胞毒性，并废除了DNA损伤剂利达霉素（LDM）在具有不同p53状态的HCT116细胞中诱导的细胞毒性和废除G（2）/ M检查点。我们的研究结果表明，与H3C116 p53（-/-）细胞相比，Chk1敲除可通过废除G（2）/ M停滞和增加细胞凋亡来增强LDM的细胞毒性，而不是p53（wt）细胞。由Chk1敲低LDM诱导的G（2）/ M逮捕的废除与减少Cdc25C和Cdc2的失活的磷酸化有关。 LDM诱导的γ-H2AX在具有Chk1敲低的细胞中增加，表明DNA双链断裂（DSB）增强。此外，Chk1的敲除还激活了caspase-2和caspase-3激活的p53基因敲除细胞中LDM介导的凋亡细胞死亡。相反，Chk2的敲低对LDM诱导的G（2）/ M停滞或凋亡没有影响。此外，Chk1和Chk2的双重敲除未能获得比单独的Chk1更好的功效。两者合计，我们建议Chk1是潜在的治疗目标，使人类p53缺陷的癌细胞对LDM敏感。

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