Aquaporin 3 facilitates chemoresistance in gastric cancer cells to cisplatin via autophagy.

Xuqiang Dong,Yangchun Zhou,Jianfei Wen,Lizong Shen,Yao Wang,Shoulin Wang

doi:10.1038/cddiscovery.2016.87

Abstract

Cisplatin (cDDP) remains one of the first-line chemotherapeutic agents for gastric cancer (GC) treatment, and resistance to cDDP is the major limitation in its clinical application. Mechanisms of cDDP resistance have been shown to be varied and complicated. Aquaporin 3 (AQP3) has been demonstrated to be overexpressed in GC tissues and is thought to be involved in GC carcinogenesis and progression. However, the role of AQP3 in chemosensitivity of GC to cytotoxic agents remains unknown. In this study, we show that AQP3 overexpression induced resistance to cDDP in AGS cells (P<0.05), and AQP3 knockdown increased the chemosensitivity in MGC803 and SGC7901 cells (P<0.05). Moreover, cDDP treatment enhanced AQP3 expression in MGC803, SGC7901 and AGS cells. AQP3 overexpression promoted the conversion of LC3-I to LC3-II in AGS cells, whereas AQP3 knockdown inhibited this conversion in MGC803 and SGC7901 cells. AQP3 upregulation increased Atg5 and Beclin-1 expression, and inhibited P62 expression in AGS cells, whereas AQP3 knockdown showed the opposite results in MGC803 and SGC7901 cells. Chloroquine (CQ), an autophagy inhibitor, enhanced the cytotoxicity of cDDP in GC cells, and CQ reversed the chemoresistance to cDDP caused by AQP3 overexpression in GC cells. Together, our data demonstrate that AQP3 facilitates cisplatin resistance in gastric cancer cells via autophagy, and suggest that the development of AQP3-based tumor therapeutics could play a key role in future GC treatment strategies.

Highlights

Gastric carcinoma (GC) remains one of the most common and lethal malignancies worldwide, especially in China.[1]
We show that Aquaporin 3 (AQP3) overexpression induced resistance to cDDP in AGS cells (Po0.05), and AQP3 knockdown increased the chemosensitivity in MGC803 and SGC7901 cells (Po0.05)
We showed for the first time that AQP3 mediates chemoresistance in gastric cancer cells to cisplatin, enhances autophagy of gastric cancer cells and the lysosome inhibitor chloroquine reverses the chemoresistance induced by AQP3

Summary

INTRODUCTION

Gastric carcinoma (GC) remains one of the most common and lethal malignancies worldwide, especially in China.[1] Despite the development of new therapeutic strategies in recent decades, radical surgery and platinum-based chemotherapy are still the standard treatments for GC, and cisplatin (cis-diamminedichloroplatinum (cDDP)) is one of the first-line chemotherapeutic agents for GC.[2] Cisplatin exerts its cytotoxic effect predominantly by forming intrastrand crosslinks in DNA that block transcription and DNA replication, resulting in cell apoptosis.[3] resistance to cDDP in GC is increasing, leading to a major limitation in its clinical application.[4] Mechanisms of cDDP resistance are complicated, including decreased drug uptake, increased drug efflux, increased DNA damage repair, alterations in apoptotic signaling pathways[5] and induced autophagy.[6] Understanding the mechanism of cDDP resistance is crucial for GC therapy. AQP3 overexpression has been demonstrated to contribute to chemoresistance in melanoma to arsenite,[14] little is known about its role in chemosensitivity of GC to cytotoxic agents. Our results demonstrate that AQP3 facilitates cisplatin resistance in gastric cancer cells via autophagy

RESULTS

DISCUSSION

COMPETING INTEREST