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首页> 外文期刊>Cell death and differentiation >Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction
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Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

机译：Isthmin靶向细胞表面GRP78，并通过诱导线粒体功能障碍触发细胞凋亡

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Isthmin (ISM) is a secreted 60-kDa protein that potently induces endothelial cell (EC) apoptosis. It suppresses tumor growth and angiogenesis in mice when stably overexpressed in cancer cells. Although alpha v beta 5 integrin serves as a low-affinity receptor for ISM, the mechanism by which ISM mediates antiangiogenesis and apoptosis in ECs remain to be fully resolved. In this work, we report the identification of cell-surface glucose-regulated protein 78 kDa (GRP78) as a high-affinity receptor for ISM (K-d = 8.6 nM). We demonstrated that ISM-GRP78 interaction triggers apoptosis not only in activated ECs but also in cancer cells expressing high level of cell-surface GRP78. Normal cells and benign tumor cells tend to express low level of cell-surface GRP78 and are resistant to ISM-induced apoptosis. Upon binding to GRP78, ISM is internalized into ECs through clathrin-dependent endocytosis that is essential for its proapoptotic activity. Once inside the cell, ISM co-targets with GRP78 to mitochondria where it interacts with ADP/ATP carriers on the inner membrane and blocks ATP transport from mitochondria to cytosol, thereby causing apoptosis. Hence, ISM is a novel proapoptotic ligand that targets cell-surface GRP78 to trigger apoptosis by inducing mitochondrial dysfunction. The restricted and high-level expression of cell-surface GRP78 on cancer cells and cancer ECs make them uniquely susceptible to ISM-targeted apoptosis. Indeed, systemic delivery of recombinant ISM potently suppressed subcutaneous 4T1 breast carcinoma and B16 melanoma growth in mice by eliciting apoptosis selectively in the cancer cells and cancer ECs. Together, this work reveals a novel ISM-GRP78 apoptosis pathway and demonstrates the potential of ISM as a cancer-specific and dual-targeting anticancer agent.
机译：Isthmin（ISM）是一种分泌的60 kDa蛋白，可有效诱导内皮细胞（EC）凋亡。当在癌细胞中稳定过量表达时，它可以抑制小鼠的肿瘤生长和血管生成。尽管αv beta 5整联蛋白可作为ISM的低亲和力受体，但ISM介导EC中抗血管生成和凋亡的机制仍有待完全解决。在这项工作中，我们报告鉴定细胞表面葡萄糖调节蛋白78 kDa（GRP78）作为ISM的高亲和力受体（K-d = 8.6 nM）。我们证明，ISM-GRP78相互作用不仅在活化的EC中触发凋亡，而且在表达高水平细胞表面GRP78的癌细胞中也触发凋亡。正常细胞和良性肿瘤细胞倾向于表达低水平的细胞表面GRP78，并且对ISM诱导的细胞凋亡具有抵抗力。结合GRP78后，ISM通过网格蛋白依赖性内吞作用被内化到EC中，而网格蛋白依赖性内吞作用对其促凋亡活性至关重要。进入细胞后，ISM会与GRP78共同靶向线粒体，在那里它与内膜上的ADP / ATP载体相互作用并阻止ATP从线粒体到细胞质的转运，从而导致细胞凋亡。因此，ISM是一种靶向细胞表面GRP78的新型促凋亡配体，可通过诱导线粒体功能障碍来触发细胞凋亡。细胞表面GRP78在癌细胞和癌细胞EC上的受限和高水平表达使其对ISM靶向的细胞凋亡具有独特的敏感性。确实，重组ISM的全身递送通过在癌细胞和EC中选择性诱导细胞凋亡，有效抑制了小鼠的皮下4T1乳腺癌和B16黑色素瘤的生长。总之，这项工作揭示了一种新型的ISM-GRP78细胞凋亡途径，并证明了ISM作为一种癌症特异性和双重靶向抗癌药的潜力。

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