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

被引：169

作者：

Dolma, Sonam ^{[1
,2
]}

Selvadurai, Hayden J. ^{[1
]}

Lan, Xiaoyang ^{[1
,3
]}

Lee, Lilian ^{[1
]}

Kushida, Michelle ^{[1
]}

Voisin, Veronique ^{[5
]}

Whetstone, Heather ^{[1
]}

So, Milly ^{[1
]}

Aviv, Tzvi ^{[1
]}

Park, Nicole ^{[1
,3
]}

Zhu, Xueming ^{[1
]}

Xu, ChangJiang ^{[5
]}

Head, Renee ^{[1
]}

Rowland, Katherine J. ^{[1
]}

Bernstein, Mark ^{[6
]}

Clarke, Ian D. ^{[1
,7
]}

Bader, Gary ^{[3
,5
]}

Harrington, Lea ^{[8
]}

Brumell, John H. ^{[3
,9
]}

Tyers, Mike ^{[8
]}

Dirks, Peter B. ^{[1
,2
,3
,4
]}

机构：

[1] Hosp Sick Children SickKids, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON M5G 0A4, Canada

[2] Univ Toronto, Dept Lab Med & Pathobiol, 100 Coll St, Toronto, ON M5S 1A8, Canada

[3] Univ Toronto, Dept Mol Genet, 100 Coll St, Toronto, ON M5S 1A8, Canada

[4] SickKids, Div Neurosurg, Toronto, ON M5G 1X8, Canada

[5] Univ Toronto, Donnelly Ctr Cellular & Biomed Res, Toronto, ON M5S3E1, Canada

[6] Univ Toronto, Toronto Western Hosp, Div Neurosurg, Toronto, ON M5T 2S8, Canada

[7] OCAD Univ, Sch Interdisciplinary Studies, Toronto, ON M5T 1W1, Canada

[8] Univ Montreal, Dept Med, Inst Res Immunol & Canc, Montreal, PQ H3T 1J4, Canada

[9] SickKids, Cell Biol Program, Toronto, ON M5G 0A4, Canada

来源：

CANCER CELL | 2016年 / 29卷 / 06期

基金：

欧洲研究理事会; 加拿大健康研究院;

关键词：

GROWTH-FACTOR RECEPTOR; NEURODEGENERATIVE DISEASE; SUBVENTRICULAR ZONE; ADULT NEUROGENESIS; CANCER; BRAIN; PROMOTES; DRUGS; LINES; IDENTIFICATION;

D O I：

10.1016/j.ccell.2016.05.002

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 PDGFR beta, ERK1/2, and mTOR and disrupted the autophagy-lysosomal pathway, leading to accumulation of autophagic vacuoles followed by G(0)/G(1) arrest and apoptosis. These results demonstrate a role for neurochemical pathways in governing GBM stem cell proliferation and suggest therapeutic approaches for GBM.

引用

页码：859 / 873

页数：15

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