Stepczynska A, Lauber K, Engels I H, Janssen O, Kabelitz D, Wesselborg S, Schulze-Osthoff K
Department of Immunology and Cell Biology, University of Münster, Germany.
Oncogene. 2001 Mar 8;20(10):1193-202. doi: 10.1038/sj.onc.1204221.
Apoptosis can be induced by various stimuli including DNA-damaging anticancer drugs and the protein kinase inhibitor staurosporine. It is generally believed that the molecular events during execution of apoptosis are shared, as both anticancer drugs and staurosporine derivatives induce mitochondrial damage, cytochrome c release and the activation of the caspase-9 proteolytic cascade. In the present study we show that overexpression of a dominant-negative caspase-9 mutant abolished the activation of endogenous caspase-9, caspase-3 and the cleavage of the caspase substrate Bid in response to anticancer drug treatment. Surprisingly, however, only marginal effects were observed during staurosporine-induced apoptosis. Furthermore, we describe a Jurkat T-cell clone that is completely resistant towards different anticancer drugs, but remains sensitive towards staurosporine-induced apoptosis. In these cells only staurosporine, but neither anti-CD95 nor anticancer drugs were able to trigger caspase activity and the cleavage of caspase substrates. Our results therefore suggest that the mechanism of staurosporine-induced apoptosis is more complex and at least partially differs from anticancer drug-induced caspase activation. These distinct features of staurosporine may allow to bypass chemoresistance of tumor cells and may encourage further clinical trials for the use of staurosporine derivatives in antitumor therapy.
细胞凋亡可由多种刺激诱导，包括具有DNA损伤作用的抗癌药物和蛋白激酶抑制剂星形孢菌素。人们普遍认为，细胞凋亡执行过程中的分子事件是相同的，因为抗癌药物和星形孢菌素衍生物都会诱导线粒体损伤、细胞色素c释放以及半胱天冬酶-9蛋白水解级联反应的激活。在本研究中，我们发现显性负性半胱天冬酶-9突变体的过表达消除了内源性半胱天冬酶-9、半胱天冬酶-3的激活以及抗癌药物处理后半胱天冬酶底物Bid的裂解。然而，令人惊讶的是，在星形孢菌素诱导的细胞凋亡过程中仅观察到轻微影响。此外，我们描述了一种Jurkat T细胞克隆，它对不同的抗癌药物完全耐药，但对星形孢菌素诱导的细胞凋亡仍敏感。在这些细胞中，只有星形孢菌素，而抗CD95和抗癌药物均不能触发半胱天冬酶活性及半胱天冬酶底物的裂解。因此，我们的结果表明，星形孢菌素诱导细胞凋亡的机制更为复杂，至少部分不同于抗癌药物诱导的半胱天冬酶激活。星形孢菌素的这些独特特性可能有助于绕过肿瘤细胞的化疗耐药性，并可能鼓励进一步开展星形孢菌素衍生物用于抗肿瘤治疗的临床试验。
