Cell Surface GRP78 Accelerated Breast Cancer Cell Proliferation and Migration by Activating STAT3.

Xiaoli Yao,Xinghua Zhang,Xiang Li,Liang Zhang,Shengrong Sun,Hua Liu,Changhua Wang,Salvatore V Pizzo

doi:10.1371/journal.pone.0125634

Abstract

High levels of cell surface glucose regulated protein 78 (sGRP78) have been implicated in cancer growth, survival, metastasis, and chemotherapy resistance. However, the underlying mechanism remains largely unknown. Here we report that the level of sGRP78 expression in human breast tumors gradually increases during cancer progression. Overexpression of GRP78 significantly enhanced its membrane distribution in human MCF-7 breast cancer cells, but had no effect on endoplasmic reticulum (ER) stress. High levels of sGRP78 facilitated cell proliferation and migration, as well as suppressed cell apoptosis. Neutralization of sGRP78 by a specific antibody against GRP78 alleviated sGRP78-induced cell growth and migration. Importantly, high phosphorylation levels of the signal transducer and activator of transcription 3 (STAT3) were found in human breast tumors that express sGRP78 and MCF-7 cells infected with adenovirus encoding human GRP78. Pretreatment with a GRP78 antibody suppressed STAT3 phosphorylation. Furthermore, genetic and pharmacological inhibition of STAT3 reversed the impacts of GRP78 on cell proliferation, apoptosis, and migration. These findings indicate that STAT3 mediates sGRP78-promoted breast cancer cell growth and migration.

Highlights

Glucose regulated protein 78 (GRP78, known as binding immunoglobulin protein (BiP)) is a multi-functional protein predominantly expressed in the lumen of the endoplasmic reticulum (ER)
We firstly analyzed a series of paired human breast tumors and adjacent non-tumor tissues for the expression pattern of cell surface GRP78 by immunofluorescence (IF). sGRP78 location was determined by co-localization with the membrane marker protein E-cadherin
We show that sGRP78 is a novel regulator in modulating cell growth and metastasis in breast cancer cells

Summary

Introduction

Glucose regulated protein 78 (GRP78, known as binding immunoglobulin protein (BiP)) is a multi-functional protein predominantly expressed in the lumen of the endoplasmic reticulum (ER). GRP78 acts as a major ER chaperone and a master regulator of ER stress signaling through controlling protein folding and assembly, preventing protein aggregation, and regulating signaling of the unfolded protein response (UPR) [1,2,3,4]. As a central stress sensor, the level of GRP78 can be up-regulated by a variety of alterations in the tumor microenvironment, such as hypoxia, glucose or nutrient deprivation, lactic acidosis, and inflammatory.

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