IGF1 promotes resistance to apoptosis in melanoma cells through an increased expression of BCL2, BCL-X(L), and survivin
IGF1 promotes resistance to apoptosis in melanoma cells through an increased expression of BCL2, BCL-X(L), and survivin
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DOI：
10.1038/sj.jid.5701185
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发表时间：
2008-06-01
影响因子：
6.5
通讯作者：
Bertolotto, Corine
中科院分区：
文献类型：
--
作者：
Hilmi, Caroline;Larribere, Lionel;Bertolotto, Corine
IGF 1在多种肿瘤的发展和生长以及细胞凋亡的预防中起着关键作用。在黑色素瘤细胞中，IGF 1已被证明介导对失巢凋亡诱导的细胞凋亡的抵抗。然而，IGF 1对其他促凋亡刺激的影响从未报道过。此外，IGF 1介导其在黑色素瘤细胞中促生存特性的分子机制仍然未知。在这里，我们表明，IGF 1损害肿瘤坏死因子相关的凋亡诱导配体和星形孢菌素诱导的细胞凋亡表达野生型或致癌B-Raf的黑色素瘤细胞的发病。此外，我们表明，IGF 1抑制线粒体损伤，发生在细胞凋亡，从而表明IGF 1的行为在线粒体水平介导其抗凋亡刺激。因此，IGF 1增加BCL 2家族抗凋亡成员BCL 2和BCL-X（L）的mRNA水平和蛋白表达，以及凋亡蛋白抑制剂生存素的mRNA水平和蛋白表达。此外，它们通过小干扰RNA的特异性沉默阻止了IGF 1的保护作用。因此，这些发现描绘了IGF 1介导其促生存特性的分子机制，并为旨在中和IGF 1或其靶基因的临床策略提供了基础。
IGF1 plays a key role in the development and growth of multiple tumors and in the prevention of apoptosis. In melanoma cells, IGF1 has been shown to mediate resistance to anoikis-induced apoptosis. However, the effect of IGF1 on other proapoptotic stimuli has never been reported. Further, the molecular mechanisms by which IGF1 mediates its prosurvival properties in melanoma cells remain unknown. Here, we demonstrate that IGF1 impairs the onset of tumor necrosis factor-related apoptosis-inducing ligand and staurosporine-induced apoptosis in melanoma cells expressing either wild-type or oncogenic B-Raf. Further, we show that IGF1 inhibits mitochondrial damage that occurs during apoptosis, thereby indicating that IGF1 acts at the level of mitochondria to mediate its antiapoptotic stimuli. Accordingly, IGF1 increases the mRNA levels and protein expression of antiapoptotic members of the BCL2 family-BCL2 and BCL-X(L)-and that of the inhibitor of apoptosis protein, survivin. Further, their specific silencing by small interfering RNA prevents the protective effect of IGF1. These findings therefore delineate the molecular mechanisms by which IGF1 mediates its prosurvival properties and provide a basis for clinical strategies designed to neutralize IGF1 or its target genes.