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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：我们之前已经证明，Bim是主要的BH3-only蛋白，取代Bcl-xl中的Bak/Bax，以非p53依赖的方式激活前列腺癌细胞凋亡，从而对阿霉素产生应答。然而，在携带p53野生型的LNCaP细胞和携带p53缺失的PC3细胞之间，阿霉素治疗的比较表明，p53可能是最大化凋亡的关键。ATM的抑制并不影响阿霉素诱导的细胞凋亡。p53的过度表达并不影响ABT-263诱导的细胞凋亡，然而，与阿霉素或ABT-263单独使用相比，阿霉素与ABT-263联合使用诱导的细胞凋亡反应更高。这些结果表明，阿霉素诱导的DNA损伤控制p53的功能，从而加剧细胞凋亡。事实上，在高浓度阿霉素诱导LNCaP细胞严重DNA损伤的情况下，p53的过度表达只会增强细胞凋亡。免疫荧光染色显示LNCaP细胞中出现模糊的γH2AX病灶和增大的细胞核，以响应高浓度阿霉素，导致细胞凋亡。此外，我们的结果显示，拓扑异构酶的催化抑制剂CFS-1686诱导的DNA复制应激反应中的细胞凋亡与p53无关。有趣的是，阿霉素与CFS-1686的结合同时产生DNA损伤和复制应激，从而在前列腺癌细胞中产生协同凋亡效应。因此，我们得出结论，至少在前列腺癌中，p53是DNA损伤应激而非DNA复制应激下细胞凋亡增强的传感器。

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