OCAD University Open Research Repository

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

Dolma, Sonam and Selvadurai, Hayden J. and Lan, Xiaoyang and Lee, Lilian and Kushida, Michelle and Voisin, Veronique and Whetstone, Heather and So, Milly and Aviv, Tzvi and Park, Nicole and Zhu, Xueming and Xu, ChangJiang and Head, Renee and Rowland, Katherine J. and Bernstein, Mark and Clarke, Ian D. and Bader, Gary and Harrington, Lea and Brumell, John H. and Tyers, Mike and Dirks, Peter B. (2016) Inhibition of Dopamine Receptor D4 Impedes Autophagic Flux, Proliferation, and Survival of Glioblastoma Stem Cells. Cancer Cell, 29 (6). pp. 859-873. ISSN 15356108

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Official URL: https://doi.org/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.

Item Type: Article
Divisions: Faculty of Liberal Arts & Sciences
Date Deposited: 21 Mar 2018 14:29
Last Modified: 21 Mar 2018 14:29
URI: http://openresearch.ocadu.ca/id/eprint/2204

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