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首页> 外文期刊>Carcinogenesis >The melanoma-associated antigen MAGE-D2 suppresses TRAIL receptor 2 and protects against TRAIL-induced apoptosis in human melanoma cells
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The melanoma-associated antigen MAGE-D2 suppresses TRAIL receptor 2 and protects against TRAIL-induced apoptosis in human melanoma cells

机译：黑色素瘤相关抗原MAGE-D2抑制TRAIL受体2并防止TRAIL诱导的人黑色素瘤细胞凋亡

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Emerging evidence has pointed to biological roles of melanoma-associated antigens (MAGEs) in cancer development, progression and resistance to treatment. However, the mechanisms involved remain to be fully elucidated. In this report, we show that one of the MAGE proteins, MAGE-D2, suppresses the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 2 (TRAIL-R2) and plays an important role in protecting melanoma cells from apoptosis induced by TRAIL. MAGE-D2 was commonly expressed at increased levels in melanoma cells compared with melanocytes. Although its inhibition by small interfering RNA (siRNA) did not cause cell death, it rendered melanoma cells more sensitive to TRAIL-induced apoptosis. This was associated with enhanced formation of TRAIL death-inducing signaling complex and up-regulation of TRAIL-R2, and was blocked by a recombinant TRAIL-R2/Fc chimeric protein or siRNA knockdown of TRAIL-R2. Regulation of TRAIL-R2 by MAGE-D2 appeared to be mediated by p53, in that knockdown MAGE-D2 did not up-regulate TRAIL-R2 in p53-null or mutant p53 melanoma cells. In addition, inhibition of MAGE-D2 did not result in up-regulation of TRAIL-R2 in wild-type p53 cell lines with p53 inhibited by short hairpin RNA. Indeed, knockdown of MAGE-D2 led to up-regulation of p53 due to a transcriptional increase. The regulatory effect of MAGE-D2 on TRAIL-R2 expression and TRAIL-induced apoptosis was recapitulated in studies on fresh melanoma isolates. Taken together, these results identify the expression of MAGE-D2 as an important mechanism that inhibit TRAIL-induced apoptosis and suggest that targeting MAGE-D2 may be a useful strategy in improving the therapeutic efficacy of TRAIL in melanoma.
机译：越来越多的证据表明黑素瘤相关抗原（MAGEs）在癌症的发生，发展和对治疗的抵抗力中的生物学作用。但是，所涉及的机制仍有待充分阐明。在本报告中，我们显示MAGE蛋白之一MAGE-D2抑制肿瘤坏死因子相关的凋亡诱导配体（TRAIL）死亡受体2（TRAIL-R2）的表达，并在保护黑素瘤细胞中起重要作用由TRAIL诱导的凋亡。与黑素细胞相比，MAGE-D2通常在黑素瘤细胞中以增加的水平表达。尽管其被小分子干扰RNA（siRNA）抑制并不会导致细胞死亡，但它使黑素瘤细胞对TRAIL诱导的细胞凋亡更为敏感。这与增强TRAIL诱导死亡的信号复合物的形成和TRAIL-R2的上调相关，并被重组TRAIL-R2 / Fc嵌合蛋白或TRAIL-R2的siRNA敲低所阻断。 MAGE-D2对TRAIL-R2的调节似乎是由p53介导的，因为敲低的MAGE-D2不会上调p53-null或突变的p53黑色素瘤细胞中的TRAIL-R2。另外，MAGE-D2的抑制不会导致野生型p53细胞系中的TRAIL-R2上调，而短发夹RNA会抑制p53。实际上，由于转录增加，MAGE-D2的敲低导致p53的上调。在新鲜黑素瘤分离株的研究中，概括了MAGE-D2对TRAIL-R2表达和TRAIL诱导的细胞凋亡的调节作用。综上所述，这些结果确定了MAGE-D2的表达是抑制TRAIL诱导的细胞凋亡的重要机制，并提示靶向MAGE-D2可能是提高TRAIL在黑色素瘤治疗中的有用策略。

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