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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Autocrine regulation of mda-7/IL-24 mediates cancer-specific apoptosis
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Autocrine regulation of mda-7/IL-24 mediates cancer-specific apoptosis

机译：自分泌调节mda-7 / IL-24介导癌症特异性凋亡

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摘要

A noteworthy aspect of melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) as a cancer therapeutic is its ability to selectively kill cancer cells without harming normal cells. Intracellular MDA-7/IL-24 protein, generated from an ad-enovirus expressing mda-7/IL-24 (Ad.mda-7), induces cancer-specific apoptosis by inducing an endoplasmic reticulum (ER) stress response. Secreted MDA-7/IL-24 protein, generated from cells infected with Ad.mda-7, induces growth inhibition and apoptosis in surrounding noninfected cancer cells but not in normal cells, thus exerting an anti-tumor "bystander" effect. The present studies reveal a provocative finding that recombi-nant MDA-7/IL-24 protein can robustly induce expression of endogenous mda-7/IL-24, which generates the signaling events necessary for bystander killing. To evaluate the mechanism underlying this positive autocrine feedback loop, we show that MDA-7/IL-24 protein induces stabilization of its own mRNA without activating its promoter. Furthermore, this posttran-scriptional effect depends on de novo protein synthesis. As a consequence of this autocrine feedback loop MDA-7/IL-24 protein induces sustained ER stress as evidenced by expression of ER stress markers (BiP/GRP78, GRP94, GADD153, and phospho-elF2α) and reactive oxygen species production, indicating that both intracellular and secreted proteins activate similar signaling pathways to induce apoptosis. Thus, our results clarify the molecular mechanism by which secreted MDA-7/IL-24 protein (generated from Ad.mda-7-infected cells) exerts cancer-specific killing.
机译：黑色素瘤分化相关基因7 /白介素24（mda-7 / IL-24）作为癌症治疗剂的一个值得注意的方面是其选择性杀伤癌细胞而不损害正常细胞的能力。从表达mda-7 / IL-24（Ad.mda-7）的腺病毒中产生的细胞内MDA-7 / IL-24蛋白通过诱导内质网（ER）应激反应来诱导癌症特异性凋亡。从感染Ad.mda-7的细胞中产生的分泌的MDA-7 / IL-24蛋白在周围未感染的癌细胞中诱导生长抑制和凋亡，而在正常细胞中则没有，从而发挥了抗肿瘤“旁观者”的作用。本研究揭示了一个令人鼓舞的发现，即重组MDA-7 / IL-24蛋白可以强有力地诱导内源性mda-7 / IL-24的表达，从而产生旁观者杀死所必需的信号传递事件。若要评估潜在的这种积极的自分泌反馈回路的机制，我们表明MDA-7 / IL-24蛋白诱导其自身mRNA的稳定而不激活其启动子。此外，这种转录后的作用取决于从头蛋白质的合成。这种自分泌反馈回路的结果是，MDA-7 / IL-24蛋白诱导持续的ER应激，如ER应激标志物（BiP / GRP78，GRP94，GADD153和phospho-elF2α）的表达和活性氧的产生所证明的，这表明细胞内和分泌蛋白均激活相似的信号传导途径以诱导凋亡。因此，我们的研究结果阐明了分泌的MDA-7 / IL-24蛋白（从受Ad.mda-7感染的细胞中产生）发挥癌症特异性杀伤作用的分子机制。

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