Winograd-Katz S E, Levitzki A
Unit of Cellular Signaling, Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
Oncogene. 2006 Nov 30;25(56):7381-90. doi: 10.1038/sj.onc.1209737. Epub 2006 Jun 19.
Cisplatin is an effective DNA-damaging antitumor agent employed for the treatment of various human cancers. In this study, we report that Cisplatin activates PKB/Akt in several cancer cell lines and that this activation is mediated by EGFR, Src and PI3-kinase. Inhibition of PI3-kinase activity decreases the survival of the cells exposed to Cisplatin, suggesting that Cisplatin-induced PKB/Akt activation may lead to Cisplatin resistance. While investigating the EGFR-dependent PKB/Akt activation in MDA-MB-468 cells, we found that the EGFR receptor undergoes a gel mobility shift upon Cisplatin treatment, which is mediated by p38(MAPK). An EGFR, in which threonine 669 was mutated to alanine (A669), is phosphorylated by p38(MAPK) to a much lesser extent, suggesting that threonine 669 is a p38 phosphorylation site. We found that Cisplatin induces EGFR internalization, which is mediated by p38(MAPK-)dependent phosphorylation of the receptor on threonine 669. Our results identify the EGFR as a new substrate of p38 and identify threonine 669 as a new phosphorylation site that regulates EGFR internalization. Together, these results suggest that Cisplatin has side effects, which may alter the signaling pattern of cancer cells and modulate the desired effects of Cisplatin treatment.
顺铂是一种有效的DNA损伤抗肿瘤药物，用于治疗多种人类癌症。在本研究中，我们报告顺铂在几种癌细胞系中激活蛋白激酶B/蛋白激酶B（PKB/Akt），且这种激活由表皮生长因子受体（EGFR）、Src和磷脂酰肌醇-3激酶（PI3-激酶）介导。抑制PI3-激酶活性会降低暴露于顺铂的细胞的存活率，这表明顺铂诱导的PKB/Akt激活可能导致顺铂耐药。在研究MDA-MB-468细胞中EGFR依赖性PKB/Akt激活时，我们发现顺铂处理后EGFR受体发生凝胶迁移率改变，这由p38丝裂原活化蛋白激酶（p38(MAPK)）介导。苏氨酸669突变为丙氨酸（A669）的EGFR被p38(MAPK)磷酸化的程度要小得多，这表明苏氨酸669是p38的磷酸化位点。我们发现顺铂诱导EGFR内化，这由受体苏氨酸669上p38(MAPK)依赖性磷酸化介导。我们的结果确定EGFR是p38的新底物，并确定苏氨酸669是调节EGFR内化的新磷酸化位点。总之，这些结果表明顺铂具有副作用，可能会改变癌细胞的信号传导模式并调节顺铂治疗的预期效果。
