The Oncogene Metadherin Modulates the Apoptotic Pathway Based on the Tumor Necrosis Factor Superfamily Member TRAIL (Tumor Necrosis Factor-related Apoptosis-inducing Ligand) in Breast Cancer
The Oncogene Metadherin Modulates the Apoptotic Pathway Based on the Tumor Necrosis Factor Superfamily Member TRAIL (Tumor Necrosis Factor-related Apoptosis-inducing Ligand) in Breast Cancer
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癌基因metadherin在乳腺癌中调节基于肿瘤坏死因子超家族成员TRAIL（肿瘤坏死因子相关凋亡诱导配体）的凋亡途径。
DOI：
10.1074/jbc.m112.395913
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发表时间：
2013-03-29
影响因子：
4.8
通讯作者：
Yang, Qifeng
中科院分区：
文献类型：
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作者：
Zhang, Ning;Wang, Xiaolong;Yang, Qifeng
Metadherin (MTDH) 是新发现的基因，在超过 40% 的乳腺癌中过度表达。最近的研究表明，MTDH 有利于致癌过程和化疗耐药性。通过许多乳腺癌细胞系和乳腺肿瘤样本，我们发现MTDH的相对表达与乳腺癌中肿瘤坏死因子相关凋亡诱导配体（TRAIL）的敏感性相关。在这项研究中，我们发现内源性 MTDH 细胞的敲低使 MDA-MB-231 细胞在体外和体内对 TRAIL 诱导的细胞凋亡敏感。相反，在 TRAIL 处理下，MCF-7 细胞中 MTDH 的稳定过表达可增强细胞存活率。从机械角度来看，MTDH 下调 caspase-8，减少 caspase-8 募集到 TRAIL 死亡诱导信号复合物中，减少 caspase-3 和聚（ADP-核糖）聚合酶-2 加工，增加 Bcl-2 表达，并刺激 TRAIL 诱导的 Akt 磷酸化，而不改变死亡受体状态。在 MDA-MB-231 乳腺癌细胞中，MTDH 下调时对 TRAIL 的敏化被 caspase 抑制剂 Z-VAD-fmk（苄氧羰基-VAD-氟甲基酮）抑制，表明 MTDH 耗尽会刺激 caspase 的激活。在 MCF-7 乳腺癌细胞中，MTDH 过表达时对 TRAIL 的抗性通过 Bcl-2 的耗竭而消除，这表明 MTDH 诱导的 Bcl-2 表达有助于 TRAIL 抗性。我们进一步证实MTDH可能部分通过抑制miR-16来控制Bcl-2的表达。总的来说，我们的结果表明 MTDH 对 TRAIL 诱导的死亡具有保护功能，即它通过 miR-16 介导的 Bcl-2 上调抑制内在凋亡途径，并通过 caspase-8 下调抑制外源性凋亡途径。
Metadherin (MTDH), the newly discovered gene, is overexpressed in more than 40% of breast cancers. Recent studies have revealed that MTDH favors an oncogenic course and chemoresistance. With a number of breast cancer cell lines and breast tumor samples, we found that the relative expression of MTDH correlated with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity in breast cancer. In this study, we found that knockdown of endogenous MTDH cells sensitized the MDA-MB-231 cells to TRAIL-induced apoptosis both in vitro and in vivo. Conversely, stable overexpression of MTDH in MCF-7 cells enhanced cell survival with TRAIL treatment. Mechanically, MTDH down-regulated caspase-8, decreased caspase-8 recruitment into the TRAIL death-inducing signaling complex, decreased caspase-3 and poly(ADP-ribose) polymerase-2 processing, increased Bcl-2 expression, and stimulated TRAIL-induced Akt phosphorylation, without altering death receptor status. In MDA-MB-231 breast cancer cells, sensitization to TRAIL upon MTDH down-regulation was inhibited by the caspase inhibitor Z-VAD-fmk (benzyloxycarbonyl-VAD-fluoromethyl ketone), suggesting that MTDH depletion stimulates activation of caspases. In MCF-7 breast cancer cells, resistance to TRAIL upon MTDH overexpression was abrogated by depletion of Bcl-2, suggesting that MTDH-induced Bcl-2 expression contributes to TRAIL resistance. We further confirmed that MTDH may control Bcl-2 expression partly by suppressing miR-16. Collectively, our results point to a protective function of MTDH against TRAIL-induced death, whereby it inhibits the intrinsic apoptosis pathway through miR-16-mediated Bcl-2 up-regulation and the extrinsic apoptosis pathway through caspase-8 down-regulation.