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首页> 外文期刊>Cell death and differentiation >Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis.
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Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis.

机译：siRNA下调Bcl-2，FLIP或IAP（XIAP和survivin）可使耐药性黑色素瘤细胞对Apo2L / TRAIL诱导的细胞凋亡敏感。

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摘要

Melanoma cells are relatively resistant to Apo2L/TRAIL (TNF-related apoptosis-inducing ligand). We postulated that resistance might result from higher expression of inhibitors of apoptosis including Bcl-2, FLIP (FLICE-like inhibitory protein) or IAPs such as XIAP (X-linked inhibitor of apoptosis) or survivin. Compared to scrambled or mismatch controls, targeting individual inhibitors with siRNA (si-Bcl-2, si-XIAP, si-FLIP or si-Surv), followed by Apo2L/TRAIL resulted in marked increase in apoptosis in melanoma cells. Compared to Bcl-2 or FLIP, siRNAs against XIAP and survivin were most potent in sensitizing melanoma cells. A similar substantial increase in apoptosis was seen in renal carcinoma cells (SKRC-45, Caki-2), following the inhibition of either XIAP or survivin by siRNAs. Apo2L/TRAIL treatment in IAP-targeted cells resulted in cleavage of Bid, activation of caspase-9 and cleavage of PARP (poly ADP-ribose polymerase). Thus, Apo2L/TRAIL resistance can be overcome by interfering with expression ofinhibitors of apoptosis regulating both extrinsic (death receptor) or intrinsic (mitochondrial) pathways of apoptosis in melanoma cells.
机译：黑色素瘤细胞对Apo2L / TRAIL（TNF相关的凋亡诱导配体）具有相对抗性。我们推测抗药性可能是由凋亡抑制因子（包括Bcl-2，FLIP（FLICE样抑制蛋白）或IAAP，如XIAP（X连锁凋亡抑制因子）或survivin）的高表达引起的。与加扰或错配对照相比，以siRNA（si-Bcl-2，si-XIAP，si-FLIP或si-Surv），然后是Apo2L / TRAIL靶向单个抑制剂可导致黑素瘤细胞凋亡明显增加。与Bcl-2或FLIP相比，针对XIAP和survivin的siRNA在致敏黑素瘤细胞方面最有效。 siRNA抑制XIAP或survivin后，在肾癌细胞（SKRC-45，Caki-2）中发现了类似的凋亡实质性增加。在IAP靶向细胞中进行Apo2L / TRAIL处理可导致Bid切割，caspase-9活化和PARP（聚ADP-核糖聚合酶）切割。因此，Apo2L / TRAIL抗性可以通过干扰调节黑素瘤细胞中凋亡的外源性（死亡受体）或内在性（线粒体）途径的凋亡抑制剂的表达来克服。

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