The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies.
The critical roles of endoplasmic reticulum chaperones and unfolded protein response in tumorigenesis and anticancer therapies.
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DOI：
10.1038/onc.2012.130
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发表时间：
2013-02-14
期刊：
影响因子：
8
通讯作者：
Lee, A. S.
中科院分区：
文献类型：
--
作者：
Luo, B.;Lee, A. S.
癌症进展的特征在于需要增加蛋白质合成的快速增殖的癌细胞。因此，增强的内质网（ER）活性是必需的，以促进膜和分泌蛋白的折叠，组装和运输。这些功能由ER分子伴侣执行。现在越来越清楚的是，ER分子伴侣除了简单地促进蛋白质折叠外还具有关键功能。例如，癌症进展需要GRP 78用于癌细胞存活和增殖，以及微环境中的血管生成。GRP 78可以易位到细胞表面，作为调节致癌信号传导和细胞活力的受体。钙网蛋白是另一种内质网伴侣蛋白，它可以移位到凋亡癌细胞的细胞表面，并在体内诱导免疫原性癌细胞死亡和抗肿瘤反应。当用作抗肿瘤疫苗时，肿瘤分泌的GRP 94已经显示出引发抗肿瘤免疫应答。蛋白质二硫键异构酶是另一种ER分子伴侣，具有促癌和促生存功能。由于细胞代谢的内在改变和肿瘤微环境中的外在因素，癌细胞处于ER应激下，并且它们通过激活未折叠蛋白反应（UPR）来响应这种应激。根据ER应激的严重程度和持续时间，UPR的信号传导分支可以激活适应性和促存活信号，或诱导凋亡性细胞死亡。UPR的PERK信号传导分支在癌症增殖和存活中具有双重作用，并且也是ER应激诱导的自噬所需的。IRE 1 α分支的激活促进肿瘤发生、癌细胞存活并调节肿瘤侵袭。总之，ER稳态的扰动在肿瘤发生中起关键作用，并且ER分子伴侣和/或UPR组分的治疗性调节呈现出潜在的抗肿瘤治疗。
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 GRP78 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. Due to 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 PERK 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 IRE1α branch promotes tumorigenesis, cancer cell survival, and regulates tumor invasion. In summary, perturbance of ER homeostasis plays critical roles in tumorigenesis, and therapeutic modulation of ER chaperones and/or UPR components presents potential antitumor treatments.
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影响因子：
11.2
作者：
Dong D;Stapleton C;Luo B;Xiong S;Ye W;Zhang Y;Jhaveri N;Zhu G;Ye R;Liu Z;Bruhn KW;Craft N;Groshen S;Hofman FM;Lee AS
通讯作者：
Lee AS
影响因子：
4.8
作者：
Ding, Wen-Xing;Ni, Hong-Min;Yin, Xiao-Ming
通讯作者：
Yin, Xiao-Ming
DOI：
10.1073/pnas.0914072107
发表时间：
2010-08-31
影响因子：
11.1
作者：
Auf, Gregor;Jabouille, Arnaud;Moenner, Michel
通讯作者：
Moenner, Michel
DOI：
10.1073/pnas.220247197
发表时间：
2000-11-07
影响因子：
11.1
作者：
Brewer, JW;Diehl, JA
通讯作者：
Diehl, JA
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D