Inhibition of Dopamine Receptor D4 Impedes Autophagic Flux, Proliferation, and Survival of Glioblastoma Stem Cells.
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.
Arthur 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.
Sonam
S
Dolma
Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada.
Hayden J
HJ
Selvadurai
Arthur 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.
Xiaoyang
X
Lan
Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada.
Lilian
L
Lee
Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada.
Michelle
M
Kushida
Donnelly Center for Cellular and Biomedical Research, University of Toronto, Toronto M5S3E1, Canada.
Veronique
V
Voisin
Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada.
Heather
H
Whetstone
Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada.
Milly
M
So
Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada.
Tzvi
T
Aviv
Arthur 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.
Nicole
N
Park
Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada.
Xueming
X
Zhu
Donnelly Center for Cellular and Biomedical Research, University of Toronto, Toronto M5S3E1, Canada.
ChangJiang
C
Xu
Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada.
Renee
R
Head
Arthur and Sonia Labatt Brain Tumor Research Center and Developmental and Stem Cell Biology, The Hospital for Sick Children (SickKids), Toronto, ON M5G 0A4, Canada.
Katherine J
KJ
Rowland
Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, ON M5T 2S8, Canada.
Mark
M
Bernstein
Arthur 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.
Ian D
ID
Clarke
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Center for Cellular and Biomedical Research, University of Toronto, Toronto M5S3E1, Canada.
Gary
G
Bader
Department of Medicine, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, QC H3T 1J4, Canada.
Lea
L
Harrington
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Cell Biology Program, SickKids, Toronto, ON M5G 0A4, Canada.
John H
JH
Brumell
Department of Medicine, Institute for Research in Immunology and Cancer, Université de Montreal, Montreal, QC H3T 1J4, Canada.
Mike
M
Tyers
Arthur 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.
Peter B
PB
Dirks
D000818:Animals; D001343:Autophagy; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000008:administration & dosage* / Q000494:pharmacology; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C493599:DRD4 protein, human; D054852:Small Molecule Libraries; D050638:Receptors, Dopamine D4