Cell Reports (Nov 2014)
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
Affiliations
- Christopher S. Hackett
- Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA
- David A. Quigley
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
- Robyn A. Wong
- Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA
- Justin Chen
- Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA
- Christine Cheng
- Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA
- Young K. Song
- Oncogenomics Section, Pediatric Oncology Branch, National Cancer Institute, Gaithersburg, MD 20877, USA
- Jun S. Wei
- Oncogenomics Section, Pediatric Oncology Branch, National Cancer Institute, Gaithersburg, MD 20877, USA
- Ludmila Pawlikowska
- Department of Anesthesia, University of California, San Francisco, San Francisco, CA 94143, USA
- Yun Bao
- Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA
- David D. Goldenberg
- Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA
- Kim Nguyen
- Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA
- W. Clay Gustafson
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA
- Sundari K. Rallapalli
- Departments of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA
- Yoon-Jae Cho
- Department of Neurology, Stanford University School of Medicine, Stanford, CA 94305, USA
- James M. Cook
- Departments of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA
- Serguei Kozlov
- Mouse Cancer Genetics Program, Center for Advanced Preclinical Research, National Cancer Institute, Frederick, MD 21702, USA
- Jian-Hua Mao
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA
- Terry Van Dyke
- Mouse Cancer Genetics Program, Center for Advanced Preclinical Research, National Cancer Institute, Frederick, MD 21702, USA
- Pui-Yan Kwok
- Institute for Human Genetics, University of California, San Francisco, San Francisco, CA 94143, USA
- Javed Khan
- Oncogenomics Section, Pediatric Oncology Branch, National Cancer Institute, Gaithersburg, MD 20877, USA
- Allan Balmain
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
- QiWen Fan
- Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA
- William A. Weiss
- Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA
- DOI
- https://doi.org/10.1016/j.celrep.2014.09.046
- Journal volume & issue
-
Vol. 9,
no. 3
pp. 1034 – 1046
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.
