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

Abstract

SUMMARY 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.

Neuronal activity in the glioma microenvironment

“…Low-grade glioma-bearing mice treated with the tricyclic antidepressant imipramine exhibited prolonged survival, with decreased rate of tumor cell proliferation and reduced progression to high grade lesions; the mechanism of action appears to involve induction of autophagy, leading to apoptosis (Shchors et al, 2015). Glioblastoma cells express dopamine receptors (Dolma et al, 2016; Li et al, 2014), and in a proliferation screen performed on three patient-derived glioma cell cultures exposed to a panel of neurotransmitter agonists, antagonists, and reuptake inhibitors, pharmacologic blockade of dopamine receptor D4 emerged as an effective and selective inhibitor of glioma cell proliferation via disruption of autophagy and downstream induction of apoptosis (Dolma et al, 2016). Glioma cells also express functional serotonin receptors (Mahe et al, 2004), but whether serotonergic signaling influences glioma growth or progression is less clear, as increased serotonin levels as a result of selective serotonin reuptake inhibitor (SSRI) therapy have not been shown to have a survival benefit in retrospective studies of patients with glioblastoma and comorbid depression (Caudill et al, 2011).…”

Redox-Related Epigenetic Mechanisms in Glioblastoma: Nuclear Factor (Erythroid-Derived 2)-Like 2, Cobalamin, and Dopamine Receptor Subtype 4

“…Based on the unique capability of the D 4 receptor to modulate methylation status, we suggest that the anti-glioblastoma tumor effects of D 4 receptor antagonists described by Dolma et al (12) may reflect inhibition of methylation reactions such as dopamine-stimulated PLM, which can influence the activity of receptors and transporters at the plasma membrane (80), and/or SAM-dependent methylation effects, which might include effects on autophagy. For example, increased membrane fluidity and/or membrane asymmetry promoted by D 4 receptor-mediated PLM may contribute to PDGFRβ transactivation.…”

“…Dolma et al (12) recently reported that selective D 4 receptor antagonists restrict the growth of glioblastoma stem cells in vitro and in vivo . Clonogenic activity of freshly isolated tumor cells was reduced 19- to 83-fold by these antagonists.…”

“…Although the study by Dolma et al (12) showed that the D 4 receptor is an important new antitumor target for glioblastoma, the detailed molecular mechanism underlying its unique autophagy-based effectiveness remain unclear. Like other GPCRs, the D 4 receptor exerts several G protein-mediated signaling activities, including inhibition of cyclic AMP formation.…”

“…The dopamine receptor subtype 4 (D 4 receptor) is a G protein-coupled receptor (GPCR) with neurotransmission and metabolic roles, which include effects on the redox and methylation states. D 4 receptors are expressed in glioblastoma and D 4 receptor antagonists inhibit the growth of glioblastoma stem cells (12), although the precise relationship between Nrf2 and D 4 receptors has not yet been established. This article is the first to explore the relationships between Nrf2, cobalamin, and D 4 receptors in cancer, specifically in glioblastoma.…”