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 Khan; Allan Balmain; QiWen Fan; William A Weiss

doi:10.1016/j.celrep.2014.09.046

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

Cell Rep. 2014 Nov 6;9(3):1034-46. doi: 10.1016/j.celrep.2014.09.046. Epub 2014 Oct 23.

Authors

Christopher S Hackett¹, David A Quigley², Robyn A Wong³, Justin Chen¹, Christine Cheng³, Young K Song⁴, Jun S Wei⁴, Ludmila Pawlikowska⁵, Yun Bao³, David D Goldenberg³, Kim Nguyen³, W Clay Gustafson⁶, Sundari K Rallapalli⁷, Yoon-Jae Cho⁸, James M Cook⁷, Serguei Kozlov⁹, Jian-Hua Mao¹⁰, Terry Van Dyke⁹, Pui-Yan Kwok¹¹, Javed Khan⁴, Allan Balmain², QiWen Fan¹², William A Weiss¹³

Affiliations

¹ Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
² Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Oncogenomics Section, Pediatric Oncology Branch, National Cancer Institute, Gaithersburg, MD 20877, USA.
⁵ Department of Anesthesia, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Departments of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA.
⁸ Department of Neurology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Mouse Cancer Genetics Program, Center for Advanced Preclinical Research, National Cancer Institute, Frederick, MD 21702, USA.
¹⁰ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA.
¹¹ Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
¹² Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: qiwen.fan@ucsf.edu.
¹³ Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: waweiss@gmail.com.

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 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Arginase / antagonists & inhibitors
Arginase / genetics*
Brain Neoplasms / genetics*
Cell Line, Tumor
Cell Survival
Chromosomes, Mammalian / genetics
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
gamma-Aminobutyric Acid / metabolism

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

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