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

Publication date: 13 June 2016
Source:Cancer Cell, Volume 29, Issue 6
Author(s): Sonam Dolma, Hayden J. Selvadurai, Xiaoyang Lan, Lilian Lee, Michelle Kushida, Veronique Voisin, Heather Whetstone, Milly So, Tzvi Aviv, Nicole Park, Xueming Zhu, ChangJiang Xu, Renee Head, Katherine J. Rowland, Mark Bernstein, Ian D. Clarke, Gary Bader, Lea Harrington, John H. Brumell, Mike Tyers, Peter B. Dirks
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.

Graphical abstract

Teaser

Dolma et al. show that compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected glioblastoma neural stem cells (GNS). In particular, dopamine receptor D4 antagonists disrupt the autophagy-lysosomal pathway of GNS, leading to growth arrest and apoptosis.


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