Down-Regulation of MutS Homolog 2 (MSH2) Expression by Curcumin Enhances Cytotoxicity Induced by Gemcitabine in Human Lung Adenocarcinoma Cells

Jen Chung Ko,Yun Wei Lin,Peng Fang Ma,Yuan Cheng Lin,Jyh Cheng Chen,Yi Shuan Peng,Chia Hung Wu,Hao Yu Zheng,Wen Ching Chen

doi:10.4172/2161-1165.1000332

Abstract

Gemcitabine (2′,2′-difluorodeoxycytidine) is a difluorinated analog of deoxycytidine. It is used clinically to treat patients with non-small-cell lung cancer (NSCLC). Curcumin is a yellow pigment derived from the rhizome of Curcuma longa, and has been proven to have antioxidant and antitumor properties. Human MutS homolog 2 (MSH2) is a key DNA mismatch repair protein that plays an important role in maintaining genomic stability. Depletion of MSH2 from cells can reverse resistance to certain DNA-damaging agents. In this study, exposure of human lung adenocarcinoma A549 and H1975 cells to gemcitabine increased protein phosphorylation of MKK3/6 and p38 MAPK in a time- and dose-dependent manner; this was accompanied by increased expression of MSH2 mRNA and protein. Gemcitabine-induced cytotoxicity was significantly enhanced by MSH2 siRNA transfection or inactivation of p38 MAPK by SB202190 or p38 MAPK siRNA transfection. However, overexpression of MSH2 cDNA reduced gemcitabine-induced cytotoxicity. Furthermore, curcumin enhanced gemcitabine-induced cytotoxicity via inactivation of MKK3/6-p38 MAPK and downregulation of MSH2. Enforced expression of constitutively active MKK6 rescued cell viability and restored MSH2 protein levels that were suppressed by curcumin and gemcitabine. Suppression of MSH2 expression and a combination with curcumin may be considered as potential therapeutic modalities for gemcitabine-resistant NSCLC cells.

Highlights

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death in the world [1], and the majority of patients with NSCLC present with advanced metastatic stages [2]
We examined the effects of gemcitabine on signal molecules in 2 human lung adenocarcinoma cell lines, A549 and H1975
As shown in (Figure 1A), gemcitabine treatment increased MutS Homolog 2 (MSH2) protein levels, and this was accompanied by the activation of MKK3/6-p38 mitogen-activated protein kinase (MAPK) during different exposure times

Summary

Introduction

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death in the world [1], and the majority of patients with NSCLC present with advanced metastatic stages [2]. The cytotoxic chemotherapies can improve the median overall survival of NSCLC patients [3]. Gemcitabine (2′, 2′-difluorodeoxycytidine, dFdC) has been clinically utilized for NSCLC patients [4]. It′s cytotoxic effect requires intracellular transport and activation [5,6]. Down-regulation of gemcitabine-induced extracellular signal-regulated kinase 1/2 (ERK1/2) in hepatocellular and cholangiocellular carcinomas enhances cell death [10]. The molecular mechanisms leading to the lesser effectiveness of gemcitabine in lung adenocarcinoma cells than in squamous carcinoma cells in terms of growth inhibition and cytotoxicity are poorly understood and remain to be elucidated

Methods

Results

Conclusion