GRP78 Is a Targetable Receptor on Cancer and Stromal Cells.
GRP78 Is a Targetable Receptor on Cancer and Stromal Cells.
复制标题
DOI：
10.1016/j.ebiom.2018.06.030
复制
发表时间：
2018-07
期刊：
影响因子：
11.1
通讯作者：
Rangnekar VM
中科院分区：
文献类型：
--
作者：
Araujo N;Hebbar N;Rangnekar VM
Glucose-Regulated Protein 78 (GRP78), also known as BiP (Binding Immunoglobulin Protein), is a member of the Hsp70 family of chaperone proteins that is essential for embryonic development. GRP78 is highly conserved across species, and is localized primarily in the endoplasmic reticulum, where it regulates protein folding and activates the unfolded protein response pathway (UPR) during stress conditions [6]. Under normal conditions, GRP78 binds to and inactivates the ER stress sensors ATF-6, PERK and IRE1. ER stress drives the accumulation of unfolded proteins to titrate GRP78 away from the stress sensors toward plasma membrane localization. GRP78 is highly expressed on the cell surface of a variety of cancer types owing to their inherently elevated ER stress levels, and weakly expressed on normal cells [8]. Global profiling of cell surface GRP78 is highly correlated with pathological states making it a relevant target for therapy. Several natural ligands can elicit a diverse signaling response upon binding to cell surface GRP78. On tumor cells, GRP78 can bind to α2-macroglobulin and Cripto, leading to cell survival and proliferation, or to Kringle 5 and Par-4, which drives apoptosis [3]. On endothelial cells, GRP78 interacts with T-cadherin, which promotes cell survival [8]. Moreover, GRP78 antibodies, designed against the carboxylterminus, induced apoptosis of cancer cells and inhibited the growth of tumor xenografts [7]. As cell surface GRP78 agonists can trigger an apoptotic response, a considerable amount of effort has been invested in generating small molecules that can bind to cell surface GRP78 and activate the apoptotic pathways as an effective mode of anticancer therapy. Arap et al.[1] developed two targeted phage peptides containing predicted binding motifs for GRP78 wherein a dose of 300 mg/mouse was administered weekly via tail vein for four weeks. The peptides were tested in nude mice bearing DU145 prostate subcutaneous tumor xenografts and in immunocompetent Balb/c mice bearing EF43-fgf4 derived tumors. In both mouse models, the peptides were able to specifically bind GRP78, undergo cell internalization, and suppress tumor growth. Bone metastasis targeting peptidomimetic-78 (BMTP-78), a prototype drug developed by Arap et al.[1], consisting of a GRP78 binding peptide fused to a death-inducing domain, was tested in several human leukemia and lymphoma cell lines and toxicological studies were performed in rodents and nonhuman primates [9]. Remarkably, BMTP-78 reduced cell viability in 12 cell lines as well as in primary human AML cells. However, toxicology data in Sprague Dawley rats showed dose-dependent toxicity, with kidneys being the most affected organ. Moreover, BMTP-78 was found to be markedly toxic to non-human primates, causing fatal cardiac dysfunction. Although
登录
查看更多内容
影响因子：
11.1
作者：
Kao C;Chandna R;Ghode A;Dsouza C;Chen M;Larsson A;Lim SH;Wang M;Cao Z;Zhu Y;Anand GS;Ge R
通讯作者：
Ge R
影响因子：
11.2
作者：
Burikhanov R;Shrestha-Bhattarai T;Qiu S;Shukla N;Hebbar N;Lele SM;Horbinski C;Rangnekar VM
通讯作者：
Rangnekar VM
DOI：
10.1158/1078-0432.ccr-13-1106
发表时间：
2013-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Liu R;Li X;Gao W;Zhou Y;Wey S;Mitra SK;Krasnoperov V;Dong D;Liu S;Li D;Zhu G;Louie S;Conti PS;Li Z;Lee AS;Gill PS
通讯作者：
Gill PS
影响因子：
12.4
作者：
Chen, M.;Zhang, Y.;Ge, R.
通讯作者：
Ge, R.
影响因子：
3.7
作者：
Tam AB;Mercado EL;Hoffmann A;Niwa M
通讯作者：
Niwa M