ROS-independent Nrf2 activation in prostate cancer.
ROS-independent Nrf2 activation in prostate cancer.
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DOI：
10.18632/oncotarget.18724
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发表时间：
2017-09-15
期刊：
影响因子：
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通讯作者：
Minelli A
中科院分区：
文献类型：
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作者：
Bellezza I;Scarpelli P;Pizzo SV;Grottelli S;Costanzi E;Minelli A
在前列腺癌中，氧化应激和随后的 Nrf2 激活促进癌细胞的存活并获得化疗耐药性。 Nrf2 将前列腺癌与内质网应激联系起来，内质网应激是一种触发未折叠蛋白反应的事件，旨在恢复细胞稳态以及适应性生存机制。 78 kD 的葡萄糖调节蛋白/免疫球蛋白重链结合蛋白 (GRP78/BiP) 是内质网中的关键分子伴侣，当在细胞表面表达时，它充当多个信号通路的受体，增强抗凋亡和增殖信号。我们发现，在衣霉素（一种 ER 应激诱导剂）存在的情况下，GRP78/BiP 易位至 PC3 细胞表面，并证明存在 GRP78/BiP 依赖性非典型 Nrf2 激活，该激活导致对 ER 应激诱导的细胞凋亡的抵抗力增加。我们发现，即使在没有 ROS 产生的情况下，衣霉素也会引起 Nrf2 激活，并激活 Akt 信号传导，这些事件通过抗 GRP78/BiP 抗体治疗而增强。细胞表面存在的 GRP78/BiP 可用于前列腺癌的免疫治疗策略，因为抗 GRP78/BiP 抗体的阻断可能通过抑制侵袭性癌细胞中发现的几种分子保护机制来促进癌症死亡。
In prostate cancer, oxidative stress and the subsequent Nrf2 activation promote the survival of cancer cells and acquired chemoresistance. Nrf2 links prostate cancer to endoplasmic reticulum stress, an event that triggers the unfolded protein response, aiming to restore cellular homeostasis as well as an adaptive survival mechanism. Glucose-regulated protein of 78 kD /immunoglobulin heavy chain binding protein (GRP78/BiP) is a key molecular chaperone in the endoplasmic reticulum that, when expressed at the cell surface, acts as a receptor for several signaling pathways enhancing antiapoptotic and proliferative signals. We showed GRP78/BiP translocation to PC3 cell surface in the presence of tunicamycin, an ER stress inductor, and demonstrated the existence of a GRP78/BiP-dependent non-canonical Nrf2 activation, responsible for increased resistance to ER-stress induced apoptosis. We found that, even in the absence of ROS production, tunicamycin causes Nrf2 activation, and activates Akt signaling, events bulnted by anti-GRP78/BiP antibody treatment. The presence of GRP78/BiP at the cell surface might be exploited for the immunotherapeutic strategy of prostate cancer since its blockage by anti-GRP78/BiP antibodies might promote cancer death by suppressing some of the several molecular protective mechanisms found in aggressive cancer cells.