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首页> 外文期刊>Chinese science bulletin >The molecular mechanism of different sensitivity of breast cancer cell lines to TRAIL
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The molecular mechanism of different sensitivity of breast cancer cell lines to TRAIL

机译：乳腺癌细胞株对TRAIL敏感性不同的分子机制

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摘要

Although Tumor necrosis factor-related apop-tosis-inducing ligand (TRAIL) selectively induces apoptosis of various cancer cells, some caner cell lines are resistant to TRAIL-induced cell death. To investigate the molecular mechanisms underlying TRAIL-resistance, two human breast cancer cell lines, MCF-7 (resistant to TRAIL) and MDA-MB-231 (sensitive to TRAIL), were used as a model system to analyze the different sensitivities to TRAIL cyto-toxicity. PKC8 inhibitor rottlerin, but not MEK and ERK1/2 inhibitor U0126 nor PI3K inhibitor LY294002, was shown to enhance TRAIL-induced apoptosis in MCF-7 cells significantly, suggesting that PKC8 might play an important role in the resistance of MCF-7 cells to TRAIL. In contrast, rottlerin, U0126, and Ly294002had no effect on MDA-MB-231 apoptosis induced by TRAIL under the same conditions. Further experiment showed that the combination of rottlerin and TRAIL cleaved PARP in the MCF-7 cells synergistically, but not in the MDA-MB-231 cells. The role of PKC8 inTRAIL-resistant MCF-7 cells was confirmed by knocking down the endogenous PKC8 expression using RNAi technology. Furthermore, caspase-3 reconstitution in MCF-7 cells was unable to alter PKC8 expression, suggesting that innate caspase-3 deficient in thecells does not cause PKC8 high expression. These data provide evidence for the first time that PKC8 plays a critical role in breast cancer cell lines to TRAIL cytotoxicity.
机译：尽管肿瘤坏死因子相关的凋亡诱导配体（TRAIL）选择性诱导各种癌细胞的凋亡，但一些癌细胞系对TRAIL诱导的细胞死亡具有抗性。为了研究抗TRAIL的分子机制，我们使用两种人乳腺癌细胞系MCF-7（对TRAIL有抗性）和MDA-MB-231（对TRAIL敏感）作为模型系统来分析对TRAIL的不同敏感性细胞毒性。 PKC8抑制剂rottlerin，而不是MEK和ERK1 / 2抑制剂U0126或PI3K抑制剂LY294002，均能显着增强TRAIL诱导的MCF-7细胞凋亡，提示PKC8可能在MCF-7细胞对MCF-7细胞的耐药性中起重要作用落后。相反，在相同条件下，rottlerin，U0126和Ly294002对TRAIL诱导的MDA-MB-231细胞凋亡没有影响。进一步的实验表明，rottlerin和TRAIL的组合在MCF-7细胞中具有协同增效作用，但在MDA-MB-231细胞中却无协同作用。通过使用RNAi技术敲除内源性PKC8表达，证实了PKC8在TRAIL耐药MCF-7细胞中的作用。此外，MCF-7细胞中的caspase-3重组不能改变PKC8的表达，这表明该细胞中先天性caspase-3缺陷不会导致PKC8的高表达。这些数据首次证明PKC8在乳腺癌细胞系中对TRAIL细胞毒性起关键作用。

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