PLEKHA5 regulates the survival and peritoneal dissemination of diffuse-type gastric carcinoma cells with Met gene amplification

Yuko Nagamura,Makoto Miyazaki,Masako Yuki,Hideki Yamaguchi,Yoshiko Nagano,Kazuki Sasaki,Ryuichi Sakai,Kiyoko Fukami,Kazuyoshi Yanagihara

doi:10.1038/s41389-021-00314-1

Abstract

Met gene amplification has been found in a subset of malignant carcinomas, including diffuse-type gastric carcinoma (DGC), which has a poor prognosis owing to rapid infiltrative invasion and frequent peritoneal dissemination. Met is considered a promising therapeutic target for DGC. However, DGC cells with Met gene amplification eventually acquire resistance to Met inhibitors. Therefore, identification of alternate targets that mediate Met signaling and confer malignant phenotypes is critical. In this study, we conducted a phosphoproteomic analysis of DGC cells possessing Met gene amplification and identified Pleckstrin Homology Domain Containing A5 (PLEKHA5) as a protein that is tyrosine-phosphorylated downstream of Met. Knockdown of PLEKHA5 selectively suppressed the growth of DGC cells with Met gene amplification by inducing apoptosis, even though they had acquired resistance to Met inhibitors. Moreover, PLEKHA5 silencing abrogated the malignant phenotypes of Met-addicted DGC cells, including peritoneal dissemination in vivo. Mechanistically, PLEKHA5 knockdown dysregulates glycolytic metabolism, leading to activation of the JNK pathway that promotes apoptosis. These results indicate that PLEKHA5 is a novel downstream effector of amplified Met and is required for the malignant progression of Met-addicted DGC.

Highlights

Gastric cancer is one of the leading causes of cancerassociated mortality worldwide
We found that a protein called Pleckstrin Homology Domain Containing A5 (PLEKHA5) is a critical regulator of malignant phenotypes, including peritoneal dissemination, of diffuse-type gastric carcinoma (DGC) cells addicted to Met signaling
PLEKHA5 expression was detected in all the cell lines tested, its tyrosine phosphorylation tended to be higher in diffuse-type gastric cancer cell lines, especially in MKN45 and 58As9 cells, both of which have Met gene amplification[21] (Fig. 1A)

Summary

Introduction

Gastric cancer is one of the leading causes of cancerassociated mortality worldwide. There are two major histological subtypes of gastric adenocarcinomas according to the Laurén classification: intestinal and diffuse[1]. We identified Met as a major tyrosine-phosphorylated protein in DGC cells and revealed that Met is required for the growth and peritoneal dissemination of DGC cells with Met gene amplification[21]. Identification of PLEKHA5 as a tyrosine-phosphorylated protein in DGC cells with Met gene amplification

Results

Conclusion