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Cancer Cell. 2016 Jun 13;29(6):859-73. doi: 10.1016/j.ccell.2016.05.002.

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

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  • 1Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 2Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada.
  • 3Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 4Donnelly Center for Cellular and Biomedical Research, University of Toronto, Toronto M5S3E1, Canada.
  • 5Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, ON M5T 2S8, Canada.
  • 6Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada; School of Interdisciplinary Studies, OCAD University, Toronto, ON M5T 1W1, Canada.
  • 7Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Center for Cellular and Biomedical Research, University of Toronto, Toronto M5S3E1, Canada.
  • 8Department of Medicine, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, QC H3T 1J4, Canada.
  • 9Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Cell Biology Program, SickKids, Toronto, ON M5G 0A4, Canada.
  • 10Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Neurosurgery, SickKids, Toronto, ON M5G 1X8, Canada. Electronic address: peter.dirks@sickkids.ca.

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.

PMID:
27300435
DOI:
10.1016/j.ccell.2016.05.002
[PubMed - in process]
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