GRP78 secreted by colon cancer cells facilitates cell proliferation via PI3K/Akt signaling.

Rong Fu,Zhuo-Yu Li,Hai-Li Wu,Peng Yang,Zong-Wei Li

doi:10.7314/apjcp.2014.15.17.7245

Rong Fu, Zhuo-Yu Li + Show 3 more

Open Access

https://doi.org/10.7314/apjcp.2014.15.17.7245

Copy DOI

Abstract

Glucose regulated protein 78 (GRP78) is usually recognized as a chaperone in the endoplasmic reticulum. However, increasing evidence indicates that GRP78 can be translocated to the cell surface, acting as a signaling receptor for a variety of ligands. Since little is known about the secretion of GRP78 and its role in the progression of colon cancer we here focused on GRP78 from colon cancer cells, and purified GRP78 protein mimicking the secreted GRP78 was able to utilize cell surface GRP78 as its receptor, activating downstream PI3K/Akt and Wnt/β-catenin signaling and promote colon cancer cell proliferation. Our study revealed a new mode of action of autocrine GRP78 in cancer progression: secreted GRP78 binds to cell surface GRP78 as its receptor and activates intracellular proliferation signaling.

Highlights

Glucose regulated protein 78 (GRP78) is traditionally regarded as a major molecular chaperone in the endoplasmic reticulum (ER), which facilitates protein folding and assembly, protein quality control, Ca2+ binding and regulates ER stress signaling
Our study revealed a new mode of action of autocrine GRP78 in cancer progression: secreted GRP78 binds to cell surface GRP78 as its receptor and activates intracellular proliferation signaling
glutathione S-transferase (GST)-GRP78 treatment elevated the phosphorylation level of Akt (Figure 3A), while treatment with 30 μM LY294002, a PI3K inhibitor, significantly reversed the proliferative effect of GSTGRP78 (Figure 3B), suggesting that PI3K/Akt pathway is a downstream signal of secreted GRP78

Summary

Introduction

Glucose regulated protein 78 (GRP78) is traditionally regarded as a major molecular chaperone in the endoplasmic reticulum (ER), which facilitates protein folding and assembly, protein quality control, Ca2+ binding and regulates ER stress signaling. Emerging evidences indicate that GRP78 can be translocated to the cell surface and acts as a receptor for a variety of ligands, exhibiting a wide range of biological effects. Ligation of surface GRP78 by activating α2macroglobulin (α2-M*) activates MAPK and Aktdependent signaling and promotes cell proliferation of prostate cancer cells (Misra et al, 2006). Cripto protein can form a complex with GRP78 at the cell surface, inhibiting transforming growth factor signaling and enhancing cell growth (Shani et al, 2008; Kelber et al, 2009). Cell surface GRP78 promotes colorectal cancer cell migration and invasion, independent of its signaling receptor function (Li et al, 2013)

Methods

Results

Conclusion