CHIP is a novel tumor suppressor in pancreatic cancer through targeting EGFR.

Tianxiao Wang,Huihua Li,Jianwei Xu,Zhe Cao,Lei You,Zhaohui Lu,Hong Shu,Yupei Zhao,Min Li,Taiping Zhang,Li Zhou,Jian Li,Jingxuan Yang

doi:10.18632/oncotarget.1890

Abstract

Carboxyl terminus of heat shock protein 70-interacting protein (CHIP) is an E3 ubiquitin ligase that is involved in protein quality control and mediates several tumor-related proteins in many cancers, but the function of CHIP in pancreatic cancer is not known. Here we show that CHIP interacts and ubiquitinates epidermal growth factor receptor (EGFR) for proteasome-mediated degradation in pancreatic cancer cells, thereby inhibiting the activation of EGFR downstream pathway. CHIP suppressed cell proliferation, anchor-independent growth, invasion and migration, as well as enhanced apoptosis induced by erlotinib in vitro and in vivo. The expression of CHIP was decreased in pancreatic cancer tissues or sera. Low CHIP expression in tumor tissues was correlated with tumor differentiation and shorter overall survival. These observations indicate that CHIP serves as a novel tumor suppressor by down-regulating EGFR pathway in pancreatic cancer cells, decreased expression of CHIP was associated with poor prognosis in pancreatic cancer.

Highlights

Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the United States [1] with an incidence rate that is nearly equal to its mortality rate, which demonstrates the aggressiveness and lethal nature of this disease
Given that epidermal growth factor receptor (EGFR) protein is a client of Hsp90 and is www.impactjournals.com/oncotarget controlled by the ubiqutination/proteasome system, we hypothesized that CHIP could be involved in the modulation of the EGFR protein level in pancreatic cancer
Immunoprecipitation and immunoblot demonstrated that endogenous EGFR and CHIP interact with each other in BxPC-3 cells (Figure 1Bi); the His-EGFR and FlagCHIP that were both expressed after plasmid transfection in BxPC-3 cells can interact with each other (Figure 1Bii)

Summary

Introduction

Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the United States [1] with an incidence rate that is nearly equal to its mortality rate, which demonstrates the aggressiveness and lethal nature of this disease. Given the low overall response rates to traditional chemotherapy, novel therapeutic targets are urgently needed for this malignant disease. EGFR is a transmembrane glycoprotein that is conserved and overexpressed in pancreatic cancer[3, 4]. It is a member of the ErbB family of receptors and has tyrosine kinase activity. EGFR over-expression is thought to confer a poor survival, correlating with a more advanced stage and the presence of metastases in pancreatic cancer. Inhibition of the EGFR signaling pathway is an attractive therapeutic target. A phase III study demonstrated a significant survival benefit associated with this targeted agent combined with gemcitabine in advanced pancreatic cancer [6]. Previous reports have established that patients rapidly www.impactjournals.com/oncotarget developed resistance, which was most likely caused by a shorter EGFR intron 1 CA repeat length [7], the mutation of KRAS[8], and the amplification of c-Met[9] in pancreatic cancer or other tumors

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Results

Conclusion