BIP/GRP78 is an intracellular target for MDA-7/IL-24 induction of cancer-specific apoptosis
BIP/GRP78 is an intracellular target for MDA-7/IL-24 induction of cancer-specific apoptosis
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DOI：
10.1158/0008-5472.can-06-0577
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发表时间：
2006-08-15
期刊：
影响因子：
11.2
通讯作者：
Fisher, Paul B.
中科院分区：
文献类型：
--
作者：
Gupta, Pankaj;Walter, Mark R.;Fisher, Paul B.
黑色素瘤分化相关基因-7/白细胞介素-24（mda-7/IL-24）是IL-10基因家族的独特成员，其在细胞培养和动物模型中在广泛的人类癌症中诱导癌症选择性生长抑制和凋亡。此外，最近的临床试验证实了mda-7/IL-24在各种实体癌和黑色素瘤患者中的安全性并记录了其显著的临床活性。尽管进行了深入的研究，但肿瘤细胞选择性mda-7/IL-24的分子基础尚未得到很好的表征。使用缺失分析，MDA-7/IL-24，M4，由氨基酸104至206组成的特定突变体被描述为保留全长蛋白的癌症特异性生长抑制和肿瘤诱导特性。采用合理设计的突变分析，我们表明，MDA-7/IL-24和M4物理相互作用BiP/GRP 78通过其C和F螺旋，定位在内质网，并激活p38 MAPK和GADD基因表达，最终在癌症选择性凋亡。这些研究通过阐明BiP/GRP 78作为确定的细胞内作用靶点，为MDA-7/IL-24的鉴别抗肿瘤活性提供了新的机制见解，并提供了开发这种癌症特异性肿瘤诱导细胞因子的改进治疗版本的无与伦比的机会。
Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a unique member of the IL-10 gene family that induces cancer-selective growth suppression and apoptosis in a wide spectrum of human cancers in cell culture and animal models. Additionally, recent clinical trials confirm safety and document significant clinical activity of mda-7/IL-24 in patients with diverse solid cancers and melanomas. Despite intensive study the molecular basis of tumor-cell selectivity of mda-7/IL-24 is not well characterized. Using deletion analysis, a specific mutant of MDA-7/IL-24, M4, consisting of amino acids 104 to 206,is described that retains the cancer-specific growth-suppressive and apoptosis-inducing properties of the full-length protein. Employing rationally designed mutational analysis, we show that MDA-7/IL-24 and M4 physically interact with BiP/GRP78 through their C and F helices, localize in the endoplasmic reticulum, and activate p38 MAPK and GADD gene expression, culminating in cancer-selective apoptosis. These studies provide novel mechanistic insights into the discriminating antitumor activity of MDA-7/IL-24 by elucidating BiP/GRP78 as a defined intracellular target of action and present an unparalleled opportunity to develop improved therapeutic versions of this cancer-specific apoptosis-inducing cytokine.