Jeong Ji-Hak, Nakajima Hiroo, Magae Junji, Furukawa Chiharu, Taki Keiko, Otsuka Kensuke, Tomita Masanori, Lee In-Seon, Kim Cheorl-Ho, Chang Hyeun-Wook, Min Kwan-Sik, Park Kwang-Kyun, Park Kwan-Kyu, Chang Young-Chae
Research Institute of Biomedical Engineering, Catholic University of Daegu School of Medicine, Daegu, Korea.
Int J Cancer. 2009 Jun 15;124(12):2797-803. doi: 10.1002/ijc.24259.
Ascochlorin, a prenylphenol antitumor antibiotic, profoundly increases the expression of endogenous p53 by increasing protein stability in the human osteosarcoma cells and human colon cancer cells. Ascochlorin also increases DNA binding activity to the p53 consensus sequence in nuclear extract and enhances transcription of p53 downstream targets. Ascochlorin specifically induces p53 phosphorylation at ser 392 without affecting ser 15 or 20, whereas DNA damaging agents typically phosphorylate these serines. Moreover, ascochlorin does not induce phosphorylation of ATM and CHK1, an established substrate of ATR that is activated by genotoxins, nor does it increase DNA strand break, as confirmed by comet assay. The structure-activity relationship suggests that p53 activation by ascochlorin is related to inhibition of mitochondrial respiration, which is further supported by the observation that respiratory inhibitors activate p53 in a manner similar to ascochlorin. These results suggest that ascochlorin, through the inhibition of mitochondrial respiration, activates p53 through a mechanism distinct from genotoxins.
曲古抑菌素，一种异戊烯基苯酚类抗肿瘤抗生素，通过提高人骨肉瘤细胞和人结肠癌细胞中的蛋白质稳定性，显著增加内源性p53的表达。曲古抑菌素还增加核提取物中与p53共有序列的DNA结合活性，并增强p53下游靶点的转录。曲古抑菌素特异性诱导丝氨酸392处的p53磷酸化，而不影响丝氨酸15或20，而DNA损伤剂通常使这些丝氨酸磷酸化。此外，曲古抑菌素不会诱导ATM和CHK1的磷酸化，ATM和CHK1是由基因毒素激活的ATR的既定底物，彗星试验也证实曲古抑菌素不会增加DNA链断裂。构效关系表明，曲古抑菌素对p53的激活与线粒体呼吸的抑制有关，呼吸抑制剂以类似于曲古抑菌素的方式激活p53这一观察结果进一步支持了这一点。这些结果表明，曲古抑菌素通过抑制线粒体呼吸，通过一种不同于基因毒素的机制激活p53。
