Sauane Moira, Su Zao-Zhong, Gupta Pankaj, Lebedeva Irina V, Dent Paul, Sarkar Devanand, Fisher Paul B
Departments of Urology, Pathology, and **Neurosurgery, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9763-8. doi: 10.1073/pnas.0804089105. Epub 2008 Jul 3.
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-eIF2alpha) 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.
黑色素瘤分化相关基因-7/白细胞介素-24（mda-7/IL-24）作为一种癌症治疗药物，其一个值得注意的方面是它能够选择性地杀死癌细胞而不损害正常细胞。由表达mda-7/IL-24的腺病毒（Ad.mda-7）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。由感染Ad.mda-7的细胞产生的分泌型MDA-7/IL-24蛋白，可诱导周围未感染的癌细胞生长抑制和凋亡，但对正常细胞无此作用，从而发挥抗肿瘤“旁观者”效应。目前的研究揭示了一个引人深思的发现，即重组MDA-7/IL-24蛋白能够强烈诱导内源性mda-7/IL-24的表达，而这会产生旁观者杀伤所需的信号事件。为了评估这种正向自分泌反馈回路的潜在机制，我们发现MDA-7/IL-24蛋白可诱导自身mRNA的稳定，而不激活其启动子。此外，这种转录后效应依赖于从头合成蛋白质。作为这种自分泌反馈回路的结果，MDA-7/IL-24蛋白诱导持续的内质网应激，内质网应激标志物（BiP/GRP78、GRP94、GADD153和磷酸化eIF2α）的表达以及活性氧的产生都证明了这一点，这表明细胞内和分泌型蛋白都激活相似的信号通路来诱导凋亡。因此，我们的结果阐明了分泌型MDA-7/IL-24蛋白（由Ad.mda-7感染的细胞产生）发挥癌症特异性杀伤作用的分子机制。
