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

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

Author information

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.

PMID:
25437558
PMCID:
PMC4251494
DOI:
10.1016/j.celrep.2014.09.046
[Indexed for MEDLINE]
Free PMC Article

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