Stimulating TRPM7 suppresses cancer cell proliferation and metastasis by inhibiting autophagy.

Yanhong Xing,Yucheng Liu,Yang Zhang,Xinyan Wang,Xiangqing Wei,Wuyang Wang,Zhongheng Sui,Feng Guo,Yuqing Wang,Rong Chen,Yi Jiang,Mengmei Wu,Jiansong Qi,Chen Lu,Lin Ding,Peng Zhang,Jun-Li Cao,Nan Liu,Yuan-Hui Fei,Mengmeng Wang

doi:10.1016/j.canlet.2021.10.043

Abstract

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitous cation channel possessing kinase activity. TRPM7 mediates a variety of physiological responses by conducting flow of cations such as Ca2+, Mg2+, and Zn2+. Here, we show that the activation of TRPM7 channel stimulated by chemical agonists of TRPM7, Clozapine or Naltriben, inhibited autophagy via mediating Zn2+ release to the cytosol, presumably from the intracellular Zn2+-accumulating vesicles where TRPM7 localizes. Zn2+ release following the activation of TRPM7 disrupted the fusion between autophagosomes and lysosomes by disturbing the interaction between Sxt17 and VAMP8 which determines fusion status of autophagosomes and lysosomes. Ultimately, the disrupted fusion resulting from stimulation of TRPM7 channels arrested autophagy. Functionally, we demonstrate that the autophagy inhibition mediated by TRPM7 triggered cell death and suppressed metastasis of cancer cells in vitro, more importantly, restricted tumor growth and metastasis in vivo, by evoking apoptosis, cell cycle arrest, and reactive oxygen species (ROS) elevation. These findings represent a strategy for stimulating TRPM7 to combat cancer.

Highlights

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitous cation channel possessing kinase activity
We demonstrate that the autophagy inhibition mediated by TRPM7 triggered cell death and suppressed metastasis of cancer cells in vitro, more importantly, restricted tumor growth and metastasis in vivo, by evoking apoptosis, cell cycle arrest, and reactive oxygen species (ROS) elevation
We demonstrate that stimulating TRPM7 channels inhibits autophagy by disrupting the fusion between autophagosomes and lysosomes

Summary

Introduction

The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitous cation channel possessing kinase activity. TRPM7 is a ubiquitously expressed cationic channel located on the plasma membrane that possesses serine/threonine kinase activity[1] It is involved in a series of fundamental cellular processes and physiological responses and plays a role in embryonic development by conducting cationic flow including divalent Ca2+, Mg2+ and Zn2+ (zinc) as well as the monovalent ions K+ and Na+[2, 3]. Emerging studies suggest that a vast majority of native TRPM7 is localized in the membrane of unknown intracellular vesicles where large quantities of zinc are stored[7] This intracellular pool of TRPM7 senses oxidative stress and functions to buffer cytosolic zinc that in turn has catalytic, structural, and regulatory functions for proteins[8]. It remains debated whether autophagy is beneficial or detrimental to tumorigenesis

Objectives

Methods

Results

Discussion

Conclusion