Protein kinase Cδ and caspase-3 modulate TRAIL-induced apoptosis in breast tumor cells.
Protein kinase Cδ and caspase-3 modulate TRAIL-induced apoptosis in breast tumor cells.
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DOI：
10.1002/jcb.22786
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发表时间：
2010-11-01
影响因子：
4
通讯作者：
Reddy, Kaladhar B.
中科院分区：
文献类型：
--
作者：
Yin, Shuping;Sethi, Seema;Reddy, Kaladhar B.
该报告描述了蛋白激酶C δ（PKCδ）过表达阻止了TRAIL诱导的乳腺肿瘤细胞凋亡;然而，参与该现象的调节机制尚不完全清楚。在这项研究中，我们发现TRAIL诱导的凋亡在PKCδ过表达的MCF-7（MCF 7/PKCδ）细胞中被显著抑制。我们的数据显示，PKCδ抑制caspase-8的激活，这是TRAIL诱导的细胞凋亡的第一步，从而阻止TRAIL诱导的细胞凋亡。使用rottlerin或PKCδ siRNA抑制PKCδ可逆转PKCδ对caspase-8活化的抑制作用，从而导致TRAIL诱导的细胞凋亡。为了确定半胱天冬酶-3诱导的PKCδ裂解是否逆转其对半胱天冬酶-8的抑制，我们利用表达半胱天冬酶-3的MCF-7细胞开发了表达野生型PKCδ（MCF-7/cas-3/PKCδ）或半胱天冬酶-3裂解抗性PKCδ突变体（MCF-7/cas-3/PKCδ mut）的稳定细胞系。与表达野生型PKCδ（MCF-7/cas-3/PKCδ）的细胞相比，过表达caspase-3切割抗性PKCδ突变体（MCF-7/cas-3/PKCδmut）的细胞显著抑制TRAIL诱导的凋亡。在MCF-7/cas-3/PKCδmut细胞中，与表达野生型PKCδ（MCF-7/cas-3/PKCδ）的细胞相比，TRAIL诱导的caspase-8活化被阻断，导致细胞凋亡抑制。总之，这些结果强烈地表明PKCδ的过表达抑制半胱天冬酶-8活化，导致抑制TRAIL诱导的细胞凋亡，并且其通过rottlerin、siRNA的抑制或通过半胱天冬酶-3的切割使细胞对TRAIL诱导的细胞凋亡敏感。在临床上，PKCδ过表达肿瘤可以用PKCδ抑制剂和TRAIL的组合作为新的治疗策略来治疗。
This report describes that protein kinase C delta (PKCδ) overexpression prevents TRAIL-induced apoptosis in breast tumor cells; however, the regulatory mechanism(s) involved in this phenomenon is (are) incompletely understood. In this study, we have shown that TRAIL-induced apoptosis was significantly inhibited in PKCδ overexpressing MCF-7 (MCF7/PKCδ) cells. Our data reveal that PKCδ inhibits caspase-8 activation, a first step in TRAIL-induced apoptosis, thus preventing TRAIL-induced apoptosis. Inhibition of PKCδ using rottlerin or PKCδ siRNA reverses the inhibitory effect of PKCδ on caspase-8 activation leading to TRAIL-induced apoptosis. To determine if caspase-3-induced PKCδ cleavage reverses its inhibition on caspase-8, we developed stable cell lines that either expresses wild-type PKCδ (MCF-7/cas-3/PKCδ) or caspase-3 cleavage-resistant PKCδ mutant (MCF-7/cas-3/PKCδ mut) utilizing MCF-7 cells expressing caspase-3. Cells that overexpress caspase-3 cleavage-resistant PKCδ mutant (MCF-7/cas-3/PKCδmut) significantly inhibited TRAIL-induced apoptosis when compared to wild-type PKCδ (MCF-7/cas-3/PKCδ) expressing cells. In MCF-7/cas-3/PKCδmut cells, TRAIL-induced caspase-8 activation was blocked leading to inhibition of apoptosis when compared to wild-type PKCδ (MCF-7/cas-3/PKCδ) expressing cells. Together, these results strongly suggest that overexpression of PKCδ inhibits caspase-8 activation leading to inhibition of TRAIL-induced apoptosis and its inhibition by rottlerin, siRNA, or cleavage by caspase-3 sensitizes cells to TRAIL-induced apoptosis. Clinically, PKCδ overexpressing tumors can be treated with a combination of PKCδ inhibitor(s) and TRAIL as a new treatment strategy.
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