TRPM7 channel inhibition mediates midazolam-induced proliferation loss in human malignant glioma

Tumour Biol. 2016 Nov;37(11):14721-14731. doi: 10.1007/s13277-016-5317-2. Epub 2016 Sep 14.

Abstract

The melastatin-like transient receptor potential 7 (TRPM7) has been implicated in proliferation or apoptosis of some cancers, indicating the potential of TRPM7 as an anti-anaplastic target. Here, we identified the characteristic TRPM7 channel currents in human malignant glioma MGR2 cells, which could be blocked by a pharmacologic inhibitor Gd3+. We mined the clinical sample data from Oncomine Database and found that human malignant glioma tissues expressed higher TRPM7 mRNA than normal brain ones. Importantly, we identified a widely used clinical anesthetic midazolam as a TRPM7 inhibitor. Midazolam treatment for seconds suppressed the TRPM7 currents and calcium influx, and treatment for 48 h inhibited the TRPM7 expression. The inhibitory effect on TRPM7 accounts for the proliferation loss and G0/G1 phase cell cycle arrest induced by midazolam. Our data demonstrates that midazolam represses proliferation of human malignant glioma cells through inhibiting TRPM7 currents, which may be further potentiated by suppressing the expression of TRPM7. Our result indicates midazolam as a pharmacologic lead compound with brain-blood barrier permeability for targeting TRPM7 in the glioma.

Keywords: Calcium; Cell cycle arrest; Glioma proliferation; Midazolam; TRPM7.

MeSH terms

  • Anti-Anxiety Agents / pharmacology*
  • Apoptosis / drug effects
  • Blotting, Western
  • Calcium / metabolism*
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects*
  • Data Mining
  • Databases, Factual
  • Fluorescent Antibody Technique
  • Glioma / drug therapy*
  • Glioma / metabolism
  • Glioma / pathology
  • Humans
  • Image Processing, Computer-Assisted / methods
  • Midazolam / pharmacology*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • TRPM Cation Channels / antagonists & inhibitors*
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism
  • Tumor Cells, Cultured

Substances

  • Anti-Anxiety Agents
  • RNA, Messenger
  • RNA, Small Interfering
  • TRPM Cation Channels
  • Protein-Serine-Threonine Kinases
  • TRPM7 protein, human
  • Midazolam
  • Calcium