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TRPM7 Induces Tumorigenesis and Stemness Through Notch Activation in Glioma

Jingwei Wan1,2, Alyssa Aihui Guo3, Pendelton King1

  • 1Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA, United States.

Frontiers in Pharmacology
|December 31, 2020
PubMed

Insights

Transient Receptor Potential Melastatin-related 7 (TRPM7) drives glioma stemness by activating Notch1 signaling, upregulating CD133 and ALDH1. Targeting TRPM7 or Notch1 inhibits glioblastoma growth and promotes apoptosis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Neuro-oncology

Background:

  • Transient Receptor Potential Melastatin-related 7 (TRPM7) is implicated in regulating glioma stem cell (GSC) growth and proliferation.
  • The precise mechanisms by which TRPM7 influences glioma stemness, particularly its interaction with Notch signaling, require further elucidation.

Purpose of the Study:

  • To determine the key contributors to TRPM7-mediated glioma stemness by investigating its role in Notch signaling.
  • To evaluate TRPM7 as a potential therapeutic target in glioblastoma multiforme (GBM).

Main Methods:

  • Analysis of TRPM7 expression in GBM using the Oncomine database.
  • Assessment of TRPM7's effect on glioma cell proliferation, cell cycle, and apoptosis via siRNA silencing, overexpression, and kinase-dead mutants.
  • Examination of the correlation between TRPM7 expression, Notch signaling activity, and GSC markers (CD133, ALDH1).
  • Investigation of the impact of targeting Notch1 on TRPM7-mediated glioma cell behavior.

Main Results:

  • TRPM7 mRNA expression is significantly elevated in various glioma subtypes, including GBM, compared to normal brain tissue.
  • TRPM7 silencing inhibits glioma cell growth by inducing cell cycle arrest (G1/S and G2/M phases) and promoting apoptosis.
  • TRPM7 expression positively correlates with Notch1 signaling activity and the expression of GSC markers CD133 and ALDH1.
  • Kinase-inactive TRPM7 mutants show reduced Notch1 activation and GSC marker expression.
  • Targeting Notch1 effectively suppresses TRPM7-induced glioma cell proliferation and enhances apoptosis.

Conclusions:

  • TRPM7 plays a critical role in maintaining glioma stemness by sustaining Notch1 signaling activation and upregulating CD133 and ALDH1.
  • TRPM7 is a significant driver of malignant glioma cell growth and invasion.
  • TRPM7 and Notch1 represent promising therapeutic targets for glioblastoma treatment.
Keywords:
Aldehyde dehydrogenase 1CD133TRPM7apoptosiscell cyclegliomamolecular targets

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