Autocrine regulation of mda-7/IL-24 mediates cancer-specific apoptosis
Autocrine regulation of mda-7/IL-24 mediates cancer-specific apoptosis
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DOI：
10.1073/pnas.0804089105
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发表时间：
2008-07-15
影响因子：
11.1
通讯作者：
Fisher, Paul B.
中科院分区：
文献类型：
--
作者：
Sauane, Moira;Su, Zao-Zhong;Fisher, Paul B.
黑色素瘤分化相关基因-7/白介素-24 （mda-7/IL-24）作为癌症治疗的一个值得注意的方面是其选择性杀死癌细胞而不伤害正常细胞的能力。表达MDA-7/IL-24的腺病毒产生的细胞内MDA-7/IL-24蛋白。mda-7)通过诱导内质网（ER）应激反应诱导癌症特异性凋亡。分泌MDA-7/IL-24蛋白，由感染Ad的细胞产生。Mda-7在周围未感染的癌细胞中诱导生长抑制和细胞凋亡，而在正常细胞中则不起作用，从而发挥抗肿瘤的“旁观者”作用。本研究揭示了一个令人兴奋的发现，重组MDA-7/IL-24蛋白可以强烈诱导内源性MDA-7/IL-24的表达，从而产生旁观者杀伤所必需的信号事件。为了评估这种正自分泌反馈回路的机制，我们发现MDA-7/IL-24蛋白在不激活其启动子的情况下诱导其自身mRNA的稳定。此外，这种转录后效应依赖于从头蛋白合成。由于这种自分泌反馈回路，MDA-7/IL-24蛋白诱导持续内质网应激，内质网应激标志物（BiP/GRP78、GRP94、GADD153和phospho-eIF2 α）的表达和活性氧的产生证明了这一点，这表明细胞内和分泌的蛋白都激活了类似的信号通路来诱导细胞凋亡。因此，我们的研究结果阐明了Ad产生的MDA-7/IL-24蛋白的分子机制。mda-7感染的细胞)发挥癌症特异性杀伤作用。
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 adenovirus 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 recombinant 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 posttranscriptional 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-eIF2 alpha) 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.