Staurosporine induces apoptosis of melanoma by both caspase-dependent and -independent apoptotic pathways.
Staurosporine induces apoptosis of melanoma by both caspase-dependent and -independent apoptotic pathways.
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DOI：
10.1158/1535-7163.187.3.2
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发表时间：
2004-02
影响因子：
5.7
通讯作者：
Xu Dong Zhang;S. Gillespie;P. Hersey
中科院分区：
文献类型：
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作者：
Xu Dong Zhang;S. Gillespie;P. Hersey
星形孢菌素长期以来在体外用作许多不同细胞类型中的凋亡引发剂，但所涉及的机制仍然知之甚少。在本研究中，我们研究了星形孢菌素在培养的黑色素瘤细胞系中的凋亡诱导潜力，并剖析了星形孢菌素诱导的凋亡信号通路。我们报告，虽然星形孢菌素激活Bax和线粒体caspase依赖性凋亡途径，它也诱导凋亡的黑色素瘤的caspase非依赖性途径。半胱天冬酶依赖的凋亡途径被激活后不久，暴露于星形孢菌素，并与释放细胞色素c和Smac/DIABLO从线粒体和裂解的聚（ADP-核糖）聚合酶和抑制剂的半胱天冬酶激活的DNA酶。该途径可被广泛的半胱天冬酶抑制剂所抑制。第二个凋亡途径，似乎是参与晚期凋亡事件是半胱天冬酶独立的半胱天冬酶抑制剂不能阻止晚期发生的凋亡。Bcl-2的过表达抑制早期发生的细胞凋亡，但不是后来，半胱天冬酶非依赖性途径。凋亡诱导因子可能是负责晚期凋亡的执行，其易位从线粒体到细胞核的细胞凋亡的晚期发病相吻合，不能被抑制的泛半胱天冬酶抑制剂或Bcl-2的过表达。我们的研究结果表明，星形孢菌素是能够绕过电阻的黑色素瘤细胞线粒体半胱天冬酶依赖的凋亡途径，因此，星形孢菌素衍生物可能需要进一步评估单独或与其他凋亡诱导剂。
Staurosporine has long been used in vitro as an initiator of apoptosis in many different cell types, but the mechanism involved remains poorly understood. In the present study, we have examined the apoptosis-inducing potential of staurosporine in cultured melanoma cell lines and dissected the staurosporine-induced apoptotic signaling pathway. We report that although staurosporine activated Bax and the mitochondrial caspase-dependent apoptotic pathway, it also induced apoptosis of melanoma by caspase-independent pathways. The caspase-dependent apoptotic pathway was activated relatively soon after exposure to staurosporine and was associated with release of cytochrome c and Smac/DIABLO from mitochondria and cleavage of poly(ADP-ribose) polymerase and inhibitor of caspase-activated DNase. This pathway was inhibitable by broad caspase inhibitors. A second apoptotic pathway that appeared to be involved in late apoptotic events was caspase independent in that inhibitors of caspases did not prevent the late onset of apoptosis. Overexpression of Bcl-2 inhibited the early onset of apoptosis but not the later, caspase-independent pathway. Apoptosis-inducing factor may be responsible for the late apoptotic execution in that its translocation from mitochondria into the nucleus coincided with the late onset of apoptosis and could not be inhibited by either a pan-caspase inhibitor or overexpression of Bcl-2. Our results indicate that staurosporine is able to bypass resistance of melanoma cells to mitochondrial caspase-dependent apoptotic pathways; hence, derivatives of staurosporine may warrant further evaluation either alone or with other apoptosis-inducing agents.