Department of Biochemistry and Molecular Biology, University of Southern California (USC) Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA 90089-9176, USA.
Oncogene. 2013 Feb 14;32(7):805-18. doi: 10.1038/onc.2012.130. Epub 2012 Apr 16.
Cancer progression is characterized by rapidly proliferating cancer cells that are in need of increased protein synthesis. Therefore, enhanced endoplasmic reticulum (ER) activity is required to facilitate the folding, assembly and transportation of membrane and secretory proteins. These functions are carried out by ER chaperones. It is now becoming clear that the ER chaperones have critical functions outside of simply facilitating protein folding. For example, cancer progression requires glucose regulated protein (GRP) 78 for cancer cell survival and proliferation, as well as angiogenesis in the microenvironment. GRP78 can translocate to the cell surface acting as a receptor regulating oncogenic signaling and cell viability. Calreticulin, another ER chaperone, can translocate to the cell surface of apoptotic cancer cells and induce immunogenic cancer cell death and antitumor responses in vivo. Tumor-secreted GRP94 has been shown to elicit antitumor immune responses when used as antitumor vaccines. Protein disulfide isomerase is another ER chaperone that demonstrates pro-oncogenic and pro-survival functions. Because of intrinsic alterations of cellular metabolism and extrinsic factors in the tumor microenvironment, cancer cells are under ER stress, and they respond to this stress by activating the unfolded protein response (UPR). Depending on the severity and duration of ER stress, the signaling branches of the UPR can activate adaptive and pro-survival signals, or induce apoptotic cell death. The protein kinase RNA-like ER kinase signaling branch of the UPR has a dual role in cancer proliferation and survival, and is also required for ER stress-induced autophagy. The activation of the inositol-requiring kinase 1α branch promotes tumorigenesis, cancer cell survival and regulates tumor invasion. In summary, perturbance of ER homeostasis has critical roles in tumorigenesis, and therapeutic modulation of ER chaperones and/or UPR components presents potential antitumor treatments.
肿瘤的进展特征是增殖迅速的肿瘤细胞需要增加蛋白质的合成。因此，需要增强内质网（ER）活性以促进膜和分泌蛋白的折叠、组装和运输。这些功能是由 ER 伴侣蛋白来执行的。现在已经很清楚，ER 伴侣蛋白除了简单地促进蛋白质折叠之外，还具有关键作用。例如，肿瘤的进展需要葡萄糖调节蛋白（GRP）78 来维持肿瘤细胞的存活和增殖，以及微环境中的血管生成。GRP78 可以转位到细胞表面，作为调节致癌信号和细胞活力的受体。另一种 ER 伴侣蛋白钙网织蛋白也可以转位到凋亡肿瘤细胞的细胞表面，诱导体内免疫原性肿瘤细胞死亡和抗肿瘤反应。已经表明，肿瘤分泌的 GRP94 用作抗肿瘤疫苗时可以引发抗肿瘤免疫反应。蛋白二硫键异构酶是另一种具有致癌和生存促进功能的 ER 伴侣蛋白。由于细胞代谢的内在改变和肿瘤微环境中的外在因素，肿瘤细胞处于内质网应激状态，它们通过激活未折叠蛋白反应（UPR）来应对这种应激。根据内质网应激的严重程度和持续时间，UPR 的信号分支可以激活适应性和生存促进信号，或诱导细胞凋亡。UPR 的蛋白激酶 RNA 样内质网激酶信号分支在肿瘤增殖和存活中具有双重作用，也是内质网应激诱导自噬所必需的。肌醇需求激酶 1α 分支的激活促进了肿瘤发生、肿瘤细胞存活，并调节了肿瘤侵袭。总之，内质网平衡的紊乱在肿瘤发生中起着关键作用，ER 伴侣蛋白和/或 UPR 成分的治疗调节为潜在的抗肿瘤治疗提供了可能。
