Variable expression of protein kinase Cε in human melanoma cells regulates sensitivity to TRAIL-induced apoptosis
Variable expression of protein kinase Cε in human melanoma cells regulates sensitivity to TRAIL-induced apoptosis
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DOI：
10.1158/1535-7163.mct-04-0332
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发表时间：
2005-04-01
影响因子：
5.7
通讯作者：
Hersey, P
中科院分区：
文献类型：
--
作者：
Gillespie, S;Zhang, XD;Hersey, P
蛋白激酶C（PKC）的激活被认为可以保护细胞免受死亡受体诱导的凋亡。然而，我们已经发现，肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的黑色素瘤细胞凋亡的PKC激活的效果不同的细胞系。用佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）预处理导致大多数黑素瘤细胞系的凋亡抑制，但那些PKC β表达相对较低的细胞对TRAIL诱导的凋亡敏感。将PKC β引入PKC ε-低细胞系逆转了PMA对TRAIL诱导的细胞凋亡的敏感性。相反，显性负性形式的PKC β导致敏感性增加。对TRAIL诱导的细胞凋亡的敏感性的变化反映在Bax的构象和其搬迁的类似变化。从细胞质到线粒体。同样，线粒体释放caspase/DIABLO的第二个caspase衍生激活剂、caspase-3的激活及其底物的加工也有一致的增加或减少。PKC的激活似乎介导其作用的线粒体上游，但下游的caspase-8和投标的预处理与PMA没有引起TRAIL死亡受体的表达水平的显着变化，caspase-8的激活水平的改变，或切割的投标。PKC激活抗凋亡细胞外信号调节激酶1/2途径，但该途径的抑制剂只能部分逆转PKC对TRAIL诱导的细胞凋亡的保护作用。这些结果提供了进一步的见解，黑色素瘤的TRAIL诱导的细胞凋亡的可变反应，并可能有助于确定响应表型与TRAIL治疗黑色素瘤。
Protein kinase C (PKC) activation is believed to protect against apoptosis induced by death receptors. We have found however that the effect of activation of PKC on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of melanoma differs between cell lines. Pretreatment with phorbol 12-myristate 13-acetate (PMA) led to inhibition of apoptosis in the majority of the melanoma cell lines, but those with relatively low PKC epsilon expression were sensitized to TRAIL-induced apoptosis. Introduction of PKC epsilon into PKC epsilon-low cell lines reversed sensitization of the cells to TRAIL-induced apoptosis by PMA. In contrast, a dominant-negative form of PKC epsilon caused an increase in sensitivity. The changes in sensitivity to TRAIL-induced apoptosis were reflected in similar changes in conformation of Bax and its relocation. from the cytosol to mitochondria. Similarly, there were concordant increases or decreases in mitochondrial release of second mitochondria-derived activator of caspase/DIABLO, activation of caspase-3, and processing of its substrates. Activation of PKC seemed to mediate its effects upstream of mitochondria but downstream of caspase-8 and Bid in that pretreatment with PMA did not cause significant changes in the expression levels of TRAIL death receptors, alterations in the levels of caspase-8 activation, or cleavage of Bid. PKC activated the antiapoptotic extracellular signal-regulated kinase 1/2 pathway, but inhibitors of this pathway only partially reversed the protective effect of PKC against TRAIL-induced apoptosis. These results provide further insights into the variable responses of melanoma to TRAIL-induced apoptosis and may help define responsive phenotypes to treatment of melanoma with TRAIL.