Laboratory of Immunology, Centre for DNA Fingerprinting and Diagnostics, Nampally, Hyderabad 500 001, India.
J Biol Chem. 2011 Mar 4;286(9):7339-47. doi: 10.1074/jbc.M110.191916. Epub 2010 Dec 14.
Doxorubicin is one of the most effective molecules used in the treatment of various tumors. Contradictory reports often open windows to understand the role of p53 tumor suppressor in doxorubicin-mediated cell death. In this report, we provide evidences that doxorubicin induced more cell death in p53-negative tumor cells. Several cells, having p53 basal expression, showed increase in p53 DNA binding upon doxorubicin treatment. Doxorubicin induced cell death in p53-positive cells through expression of p53-dependent genes and activation of caspases and caspase-mediated cleavage of cellular proteins. Surprisingly, in p53-negative cells, doxorubicin-mediated cell death was more aggressive (faster and intense). Doxorubicin increased the amount of Fas ligand (FasL) by enhancing activator protein (AP) 1 DNA binding in both p53-positive and p53-negative cells, but the basal expression of Fas was higher in p53-negative cells. Anti-FasL antibody considerably protected doxorubicin-mediated cell death in both types of cells. Activation of caspases was faster in p53-negative cells upon doxorubicin treatment. In contrast, the basal expression of Ras oncoprotein was higher in p53-positive cells, which might increase the basal expression of Fas in these cells. Overexpression of Ras decreased the amount of Fas in p53-negative cells, thereby decreasing doxorubicin-mediated aggressive cell death. Overall, this study will help to understand the much studied chemotherapeutic drug, doxorubicin-mediated cell signaling cascade, that leads to cell death in p53-positive and -negative cells. High basal expression of Fas might be an important determinant in doxorubicin-mediated cell death in p53-negative cells.
阿霉素是治疗各种肿瘤最有效的分子之一。相互矛盾的报告常常为了解抑癌基因 p53 在阿霉素介导的细胞死亡中的作用提供了线索。在本报告中，我们提供的证据表明，阿霉素在 p53 阴性肿瘤细胞中诱导更多的细胞死亡。一些具有基础 p53 表达的细胞在阿霉素处理后显示出 p53 DNA 结合增加。阿霉素通过表达 p53 依赖性基因和激活半胱天冬酶以及半胱天冬酶介导的细胞蛋白裂解，在 p53 阳性细胞中诱导细胞死亡。令人惊讶的是，在 p53 阴性细胞中，阿霉素介导的细胞死亡更为剧烈（更快、更强烈）。阿霉素通过增强 p53 阳性和 p53 阴性细胞中的激活蛋白 (AP) 1 DNA 结合，增加 Fas 配体 (FasL) 的量，但 Fas 的基础表达在 p53 阴性细胞中更高。抗 FasL 抗体在两种类型的细胞中都能显著保护阿霉素介导的细胞死亡。阿霉素处理后，p53 阴性细胞中半胱天冬酶的激活更快。相比之下，p53 阳性细胞中 Ras 癌蛋白的基础表达更高，这可能会增加这些细胞中 Fas 的基础表达。Ras 的过表达降低了 p53 阴性细胞中 Fas 的数量，从而减少了阿霉素介导的侵袭性细胞死亡。总的来说，这项研究将有助于理解研究得很多的化疗药物阿霉素介导的细胞信号级联反应，该反应导致 p53 阳性和阴性细胞的死亡。Fas 的基础高表达可能是 p53 阴性细胞中阿霉素介导的细胞死亡的一个重要决定因素。
