Expression Quantitative Trait Loci and Receptor Pharmacology Implicate Arg1 and the GABA-A Receptor as Therapeutic Targets in Neuroblastoma

• Published in: Cell reports (Cambridge) Vol. 9; no. 3; pp. 1034 - 1046
• Main Authors: Hackett, Christopher S., Quigley, David A., Wong, Robyn A., Chen, Justin, Cheng, Christine, Song, Young K., Wei, Jun S., Pawlikowska, Ludmila, Bao, Yun, Goldenberg, David D., Nguyen, Kim, Gustafson, W. Clay, Rallapalli, Sundari K., Cho, Yoon-Jae, Cook, James M., Kozlov, Serguei, Mao, Jian-Hua, Van Dyke, Terry, Kwok, Pui-Yan, Khan, Javed, Balmain, Allan, Fan, QiWen, Weiss, William A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.11.2014; Elsevier
• Subjects: Animals; Apoptosis; Arginase - antagonists & inhibitors; Arginase - genetics; Brain Neoplasms - genetics; Cell Line, Tumor; Cell Survival; Chromosomes, Mammalian - genetics; gamma-Aminobutyric Acid - metabolism; Gene Expression Regulation, Neoplastic; Genetic Association Studies; Genetic Linkage; Genetic Predisposition to Disease; Humans; Mice; Molecular Targeted Therapy; Neuroblastoma - genetics; Quantitative Trait Loci - genetics; Receptors, GABA-A - genetics; Survival Analysis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2014.09.046

The development of targeted therapeutics for neuroblastoma, the third most common tumor in children, has been limited by a poor understanding of growth signaling mechanisms unique to the peripheral nerve precursors from which tumors arise. In this study, we combined genetics with gene-expression analysis in the peripheral sympathetic nervous system to implicate arginase 1 and GABA signaling in tumor formation in vivo. In human neuroblastoma cells, either blockade of ARG1 or benzodiazepine-mediated activation of GABA-A receptors induced apoptosis and inhibited mitogenic signaling through AKT and MAPK. These results suggest that ARG1 and GABA influence both neural development and neuroblastoma and that benzodiazepines in clinical use may have potential applications for neuroblastoma therapy. [Display omitted] •Arg1 and GABA gene expression correlates with neuroblastoma formation in mice•GABA gene expression correlates with survival in human neuroblastomas•Both activation of GABA-A and inhibition of ARG1 block the growth of neuroblastoma cells•A benzodiazepine inhibits AKT and ERK and induces apoptosis in neuroblastoma cells Neuroblastoma is a pediatric tumor of peripheral neural tissue. Hackett et al. now link Arg1 and GABA with genetic susceptibility to neuroblastoma formation in mice. Expression of GABA genes correlates with survival in human tumors. GABA activation and ARG1 inhibition block the growth of neuroblastoma cells. These results identify therapeutic targets in neuroblastoma and suggest a role for these pathways in neural growth.