TRPM7 channels regulate glioma stem cell through STAT3 and Notch signaling pathways

Cell Signal. 2014 Dec;26(12):2773-81. doi: 10.1016/j.cellsig.2014.08.020. Epub 2014 Sep 2.

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults with median survival time of 14.6 months. A small fraction of cancer stem cells (CSC) initiate and maintain tumors thus driving glioma tumorigenesis and being responsible for resistance to classical chemo- and radio-therapies. It is desirable to identify signaling pathways related to CSC to develop novel therapies to selectively target them. Transient receptor potential cation channel, subfamily M, member 7, also known as TRPM7 is a ubiquitous, Ca(2+) and Mg(2+) permeable ion channels that are special in being both an ion channel and a serine/threonine kinase. In studies of glioma cells silenced for TRPM7, we demonstrated that Notch (Notch1, JAG1, Hey2, and Survivin) and STAT3 pathways are down regulated in glioma cells grown in monolayer. Furthermore, phospho-STAT3, Notch target genes and CSC markers (ALDH1 and CD133) were significantly higher in spheroid glioma CSCs when compared with monolayer cultures. The results further show that tyrosine-phosphorylated STAT3 binds and activates the ALDH1 promoters in glioma cells. We found that TRMP7-induced upregulation of ALDH1 expression is associated with increases in ALDH1 activity and is detectable in stem-like cells when expanded as spheroid CSCs. Finally, TRPM7 promotes proliferation, migration and invasion of glioma cells. These demonstrate that TRPM7 activates JAK2/STAT3 and/or Notch signaling pathways and leads to increased cell proliferation and migration. These findings for the first time demonstrates that TRPM7 (1) activates a previously unrecognized STAT3→ALDH1 pathway, and (2) promotes the induction of ALDH1 activity in glioma cells.

Keywords: ALDH1; Cancer stem cell; Glioblastoma multiforme; Notch; STAT3; TRPM7.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aldehyde Dehydrogenase 1 Family
  • Base Sequence
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Glioma / enzymology
  • Glioma / genetics
  • Glioma / metabolism*
  • Glioma / pathology*
  • Humans
  • Isoenzymes / genetics
  • Models, Biological
  • Molecular Sequence Data
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / enzymology
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Phosphotyrosine / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Real-Time Polymerase Chain Reaction
  • Receptors, Notch / metabolism*
  • Retinal Dehydrogenase / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction*
  • Subcellular Fractions / metabolism
  • TRPM Cation Channels / metabolism*
  • Up-Regulation

Substances

  • Isoenzymes
  • RNA, Messenger
  • Receptors, Notch
  • STAT3 Transcription Factor
  • TRPM Cation Channels
  • Phosphotyrosine
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A1 protein, human
  • Retinal Dehydrogenase
  • Protein-Serine-Threonine Kinases
  • TRPM7 protein, human