Department of Haematology, St. Vincent's Hospital Melbourne , Fitzroy, Australia.
Department of Medicine, University of Melbourne , Fitzroy, Australia.
Expert Rev Hematol. 2020 Nov;13(11):1201-1210. doi: 10.1080/17474086.2020.1830372. Epub 2020 Oct 18.
Glucose-regulated protein 78 (GRP78) is a stress-inducible molecular chaperone expressed within the endoplasmic reticulum where it acts as a master regulator of the unfolded protein response (UPR) pathway. At times of ER stress, activation of the UPR, a multimolecular pathway, limits proteotoxicity induced by misfolded proteins. In malignancies, including multiple myeloma which is characterized by an accumulation of misfolded immunoglobulins, GRP78 expression is increased, with notable translocation of GRP78 to the cell surface. Studies suggest cell-surface GRP78 (csGRP78) to be of prognostic significance with emerging evidence that it interacts with a myriad of co-ligands to activate signaling pathways promoting cell proliferation and survival or apoptosis.
This review focuses on the role of ER and csGRP78 in physiology and oncogenesis in multiple myeloma, addressing factors that shift the balance in GRP78 signaling from survival to apoptosis. The role of GRP78 as a potential prognostic biomarker is explored and current therapeutics in development aimed at targeting csGRP78 are addressed. We conducted a PubMed literature search using the keywords 'GRP78,' 'multiple myeloma' reviewing studies prior to 2020.
Cell-surface GRP78 expression is a potential novel prognostic biomarker in myeloma and targeting of csGRP78 is promising and requires further investigation.
葡萄糖调节蛋白 78（GRP78）是一种应激诱导的分子伴侣，在内质网中表达，作为未折叠蛋白反应（UPR）途径的主调节因子。在 ER 应激时，激活 UPR 这一多分子途径可限制错误折叠蛋白诱导的毒性。在恶性肿瘤中，包括以错误折叠免疫球蛋白积累为特征的多发性骨髓瘤，GRP78 的表达增加，GRP78 明显易位到细胞表面。研究表明，细胞表面 GRP78（csGRP78）具有预后意义，有证据表明它与众多共配体相互作用，激活信号通路，促进细胞增殖和存活或凋亡。
本综述重点关注内质网和 csGRP78 在多发性骨髓瘤中的生理和肿瘤发生中的作用，探讨使 GRP78 信号从生存转向凋亡的平衡因素。探讨了 GRP78 作为潜在预后生物标志物的作用，以及目前针对 csGRP78 的开发中的治疗方法。我们使用关键词“GRP78”、“多发性骨髓瘤”在 PubMed 上进行了文献检索，回顾了 2020 年前的研究。
细胞表面 GRP78 表达是骨髓瘤的一个潜在新型预后生物标志物，靶向 csGRP78 是有前途的，需要进一步研究。
