Inhibition of Dopamine Receptor D4 Impedes Autophagic Flux, Proliferation, and Survival of Glioblastoma Stem Cells

Cancer Cell. 2016 Jun 13;29(6):859-873. doi: 10.1016/j.ccell.2016.05.002.

Abstract

Glioblastomas (GBM) grow in a rich neurochemical milieu, but the impact of neurochemicals on GBM growth is largely unexplored. We interrogated 680 neurochemical compounds in patient-derived GBM neural stem cells (GNS) to determine the effects on proliferation and survival. Compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected GNS growth. In particular, dopamine receptor D4 (DRD4) antagonists selectively inhibited GNS growth and promoted differentiation of normal neural stem cells. DRD4 antagonists inhibited the downstream effectors PDGFRβ, ERK1/2, and mTOR and disrupted the autophagy-lysosomal pathway, leading to accumulation of autophagic vacuoles followed by G0/G1 arrest and apoptosis. These results demonstrate a role for neurochemical pathways in governing GBM stem cell proliferation and suggest therapeutic approaches for GBM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Humans
  • Mice
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / drug effects
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / pathology
  • Receptors, Dopamine D4 / antagonists & inhibitors
  • Receptors, Dopamine D4 / metabolism*
  • Signal Transduction / drug effects
  • Small Molecule Libraries / administration & dosage*
  • Small Molecule Libraries / pharmacology
  • Survival Analysis
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • DRD4 protein, human
  • Small Molecule Libraries
  • Receptors, Dopamine D4