Stimulating TRPM7 suppresses cancer cell proliferation and metastasis by inhibiting autophagy
Yanhong Xing1, Xiangqing Wei2, Meng-Meng Wang3
1Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, 209 Tongshan Rd, Xuzhou, Jiangsu 221004, China.
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.
Insights
Stimulating the TRPM7 channel releases zinc, inhibiting autophagy and promoting cancer cell death. This TRPM7 activation restricts tumor growth and metastasis, offering a novel cancer treatment strategy.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a cation channel with kinase activity, crucial for physiological processes.
- TRPM7 regulates ion flow, including Ca2+, Mg2+, and Zn2+, impacting cellular functions.
Purpose of the Study:
- To investigate the role of TRPM7 activation in autophagy regulation.
- To explore the potential of TRPM7 as a therapeutic target for cancer treatment.
Main Methods:
- Activation of TRPM7 using chemical agonists (Clozapine, Naltriben).
- Assessment of autophagy flux, autophagosome-lysosome fusion, and associated protein interactions (Sxt17, VAMP8).
- Evaluation of cancer cell death, cell cycle, ROS levels, tumor growth, and metastasis in vitro and in vivo.
Main Results:
- TRPM7 activation by agonists inhibited autophagy by mediating cytosolic Zn2+ release.
- Disrupted Zn2+ homeostasis impaired autophagosome-lysosome fusion by affecting Sxt17-VAMP8 interaction.
- TRPM7-mediated autophagy inhibition induced apoptosis, cell cycle arrest, and elevated ROS, suppressing cancer progression.
Conclusions:
- TRPM7 activation serves as a novel mechanism to inhibit autophagy.
- Targeting TRPM7 can be a viable strategy to combat cancer by inducing cell death and suppressing metastasis.
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