The Mechanisms Of Secreted GRP78on Colon Cancer Cells Proliferation

Glucose regulated protein78(GRP78) is a heat shock protein in endoplasmic reticulum (ER), whose primary role is helping proteins synthesis and assembly, and regulates ER stress signaling. GRP78is overexpressed in tumor cells and translocated to cell surface as signaling co-receptors, who plays a role in signaling transduction of tumor cells. For example, cell surface GRP78acts as a receptor for activated a2-macroglobulin activates PAK-2. Together with phosphorylation of LIMK and cofilin, It leads to increased motility for metastasis. Futher more, the complex of cripto and GRP78promotes tumor cell proliferation through inhibiting TCF-signaling. GRP78can be overexpressed and secreted into microenvironment under stress of ER in solid tumor cells. It then binds to cell surface receptors of endothelial cells. Secreted GRP78protects endothelial cells from the antiangiogenic effect of Bortezomib by activating ERK and AKT pathwaysIn this study, we firstly reported that colon cancer cells can secrete GRP78into tumor microenvironment which functions as a signaling factor. MTT assay showed that autocrine of GRP78was able to significantly affect the proliferation of colon cancer cell DLD1. The interaction between secreted GRP78and cell surface GRP78has been observed in DLD1cells by mass spectrometry and immunofluorescence staining. Furthermore, to identify how the self assoiation of GRP78lead to the proliferation of colon cancer cells, western blotting was used to test the level of p-Akt. The experiments indicated that secreted GRP78activated PI3K/AKT signaling and led to enhanced p-GSK3β.It further impacted the proteins such as β-catenin, c-myc, cyclin D1that resulte in the activation of Wnt signaling pathway and the proliferation of colon cancer cells. These findings highlight that secreted GRP78in the tumor micorenvironment may exist as a novel ligand of cell surface GRP78and plays an improtant role in tumor progression.Our results showed that, GRP78in the microenvironment functions as the ligand of cell surface GRP78. It activates pro-proliferation signal and promotes tumor cells survival and proliferation. It is deduced that secretion of GRP78may be used by the tumor cells as the mean to respond to microenvironment stresses. Microenvironment factors, such as glucose deprivation and hypxia, may lead to elevated GRP78secretion, which in turn activates prosurvival signal to resist the stress responses.