Expression quantitative trait loci and receptor pharmacology implicate Arg1 and the GABA-A receptor as therapeutic targets in neuroblastoma

Christopher S. Hackett, David A. Quigley, Robyn A. Wong, Justin Chen, Christine Cheng, Young K. Song, Jun S. Wei, Ludmila Pawlikowska, Yun Bao, David D. Goldenberg, Kim Nguyen, W. Clay Gustafson, Sundari K. Rallapalli, Yoon Jae Cho, James M. Cook, Serguei Kozlov, Jian Hua Mao, Terry Van Dyke, Pui Yan Kwok, Javed KhanAllan Balmain, Qi Wen Fan, William A. Weiss

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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 benzodiazepinemediated 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.

Original languageEnglish (US)
Pages (from-to)1034-1046
Number of pages13
JournalCell Reports
Volume9
Issue number3
DOIs
StatePublished - Jan 1 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Hackett, C. S., Quigley, D. A., Wong, R. A., Chen, J., Cheng, C., Song, Y. K., Wei, J. S., Pawlikowska, L., Bao, Y., Goldenberg, D. D., Nguyen, K., Clay Gustafson, W., Rallapalli, S. K., Cho, Y. J., Cook, J. M., Kozlov, S., Mao, J. H., Van Dyke, T., Kwok, P. Y., ... Weiss, W. A. (2014). Expression quantitative trait loci and receptor pharmacology implicate Arg1 and the GABA-A receptor as therapeutic targets in neuroblastoma. Cell Reports, 9(3), 1034-1046. https://doi.org/10.1016/j.celrep.2014.09.046