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P53 enhances apoptosis induced by doxorubicin only under conditions of severe DNA damage

机译：P53仅在严重DNA损伤的条件下增强由多柔比星引起的细胞凋亡

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We previously demonstrated that Bim is the main BH3-only protein replacing Bak/Bax from Bcl-xl to activate apoptosis in a p53-independent manner in response to doxorubicin in prostate cancer. However, the comparison of doxorubicin treatment between LNCaP cells carrying p53-wild type and PC3 cells carrying p53-null suggested that p53 might be essential for maximizing apoptosis. Inhibition of ATM did not affect doxorubicin-induced apoptosis. Overexpression of p53 did not affect ABT-263-induced apoptosis and nevertheless, the combination of doxorubicin with ABT-263 induced higher apoptotic responses than did doxorubicin or ABT-263 alone. These results advocated that doxorubicin-induced DNA damage controls p53 function for intensifying apoptosis. Indeed, overexpression of p53 only enhanced apoptosis under conditions of severe DNA damage induced by high concentrations of doxorubicin in LNCaP cells. Immunofluorescence staining showed vague gamma H2AX foci and enlarged nuclei in LNCaP cells in response to high concentrations of doxorubicin, en route to apoptosis. In addition, our results revealed that the apoptosis in response to DNA replication stress induced by CFS-1686, a catalytic inhibitor of topoisomerase, is p53-independent. Interestingly, the combination of doxorubicin with CFS-1686 generated DNA damage and replication stress simultaneously, resulting in a synergistic apoptotic effect in prostate cancer cells. Thus, we concluded that p53 is a sensor for enhanced apoptosis in response to DNA damage stress, not DNA replication stress, at least in prostate cancer.
机译：我们以前证明BIM是仅在BCL-XL中替代BK-XL的主要BH3蛋白，以响应于前列腺癌的多柔比星而以p53 - 独立的方式激活细胞凋亡。然而，携带P53-NULL的LNCAP细胞与携带P53-NULL的PC3细胞之间的多柔比蛋白治疗的比较表明p53对于最大化细胞凋亡可能是必不可少的。抑制ATM不影响多柔比蛋白诱导的细胞凋亡。 P53的过度表达不影响ABT-263诱导的细胞凋亡，然而，多柔比星与ABT-263的组合诱导凋亡响应高于单独的多柔比星或ABT-263。这些结果倡导多柔比蛋白诱导的DNA损伤控制P53用于加强细胞凋亡的功能。实际上，P53的过表达仅在LNCAP细胞中高浓度的多柔比星诱导的严重DNA损伤条件下增强了细胞凋亡。免疫荧光染色在LNCAP细胞中呈响应于高浓度的多柔比星，促进到凋亡。此外，我们的结果表明，CFS-1686催化抑制剂催化抑制剂的DNA复制应激催化抑制剂催化抑制剂的凋亡，是p53无关的。有趣的是，与CFS-1686的多柔比星的组合同时产生DNA损伤和复制应力，导致前列腺癌细胞中的协同凋亡作用。因此，我们得出结论，P53是一种用于响应DNA损伤应激而增强凋亡的传感器，至少在前列腺癌中，不是DNA复制应激。

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