TRPM2 ion channel promotes gastric cancer migration, invasion and tumor growth through the AKT signaling pathway

Shekoufeh Almasi,Wasundara Fernando,David W Hoskin,Shashi Gujar,Derek R Clements,Paola Marcato,Yassine El Hiani,Andra M Sterea

doi:10.1038/s41598-019-40330-1

Shekoufeh Almasi, Wasundara Fernando + Show 6 more

Open Access

https://doi.org/10.1038/s41598-019-40330-1

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Journal: Scientific Reports	Publication Date: Mar 12, 2019
Citations: 51	License type: open-access

Affiliation: Dalhousie University, Stanford University

Abstract

Transient Receptor Potential Melastatin-2 (TRPM2) ion channel is emerging as a great therapeutic target in many types of cancer, including gastric cancer – a major health threat of cancer related-death worldwide. Our previous study demonstrated the critical role of TRPM2 in gastric cancer cells bioenergetics and survival; however, its role in gastric cancer metastasis, the major cause of patient death, remains unknown. Here, using molecular and functional assays, we demonstrate that TRPM2 downregulation significantly inhibits the migration and invasion abilities of gastric cancer cells, with a significant reversion in the expression level of metastatic markers. These effects were concomitant with decreased Akt and increased PTEN activities. Finally, TRPM2 silencing resulted in deregulation of metastatic markers and abolished the tumor growth ability of AGS gastric cancer cells in NOD/SCID mice. Taken together, our results provide compelling evidence on the important function of TRPM2 in the modulation of gastric cancer cell invasion likely through controlling the PTEN/Akt pathway.

Highlights

Gastric cancer (GC) is one of the most aggressive types of cancer with a significant participation in cancer-related mortality worldwide
We recently demonstrated the functional expression of Transient Receptor Potential Melastatin-2 (TRPM2) as a plasma membrane ion channel in GC cells[17]
We have previously demonstrated the functional expression of TRPM2 in GC bioenergetics and survival[17]

Summary

Introduction

Gastric cancer (GC) is one of the most aggressive types of cancer with a significant participation in cancer-related mortality worldwide. Late diagnosis of the disease and metastasis spreading of gastric tumors remain the main reasons for GC mortality[2]. This makes understanding the basic cellular and molecular mechanisms of GC metastasis of high priorities towards the development of new clinical approaches to improve GC therapy. Longstanding investigations have demonstrated the central role for Akt pathway in the regulation of numerous cellular phenotypes associated with cancer metastasis including migration, invasion and the epithelial-mesenchymal transition (EMT) processes[3,4,5,6]. We demonstrated that TRPM2 contribute to the invasion and metastasis of GC via Akt-mediated EMT, and suggested TRPM2 inhibition as a potential therapeutic approach to hamper GC metastasis and improve GC treatment

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