前列腺细胞应答凋亡蛋白-4(Par-4)是一种在细胞质与细胞核中都能发挥作用的促凋亡蛋白.非常意外地,我们注意到正常细胞与癌症细胞都会自发分泌出Par-4蛋白到培养基中.同时我们也在能自发抵抗肿瘤的Par-4转基因小鼠中发现了自发分泌的Par-4蛋白.短时间的内质网应激反应可以通过蛋白转运抑制剂brefeldin A敏感通路来诱导细胞进一步分泌Par-4蛋白.Par-4蛋白的分泌与Caspase蛋白的激活与否不相关.非常有趣的是, Par-4蛋白通过与应激应答蛋白GRP78结合诱导凋亡,而GRP78只在癌细胞表面表达.Par-4与GRP78的结合诱导凋亡是通过内质网应激反应和FADD/caspase-8/caspase-3信号通路的激活实现的.而且,Trail信号通路诱导肿瘤细胞凋亡也是依赖Par-4与GRP78的结合.因此,Par-4蛋白通过激活一条涉及GRP78表面受体的外源信号通路来诱导细胞凋亡.

The Tumor Suppressor Par-4 Activates an Extrinsic Pathway for Apoptosis

Summary
    Prostate apoptosis response-4 (Par-4) is a proapoptotic protein with intracellular functions in the cytoplasm and nucleus. Unexpectedly, we noted Par-4 protein is spontaneously secreted by normal and cancer cells in culture, and by Par-4 transgenic mice that are resistant to spontaneous tumors. Short exposure to endoplasmic reticulum (ER) stress-inducing agents further increased cellular secretion of Par-4 by a brefeldin A-sensitive pathway. Secretion occurred independently of caspase activation and apoptosis. Interestingly, extracellular Par-4 induced apoptosis by binding to the stress response protein, glucose-regulated protein-78 (GRP78), expressed at the surface of cancer cells. The interaction of extracellular Par-4 and cell surface GRP78 led to apoptosis via ER stress and activation of the FADD/caspase-8/caspase-3 pathway. Moreover, apoptosis inducible by TRAIL, which also exerts cancer cell-specific effects, is dependent on extracellular Par-4 signaling via cell surface GRP78. Thus, Par-4 activates an extrinsic pathway involving cell surface GRP78 receptor for induction of apoptosis.

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