title: Expression quantitative trait loci and receptor pharmacology implicate Arg1 and the GABA-A receptor as therapeutic targets in neuroblastoma.
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.
authors.affiliation: 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.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Hackett
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Quigley
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Robyn A
authors.initials: RA
authors.lastname: Wong
authors.affiliation: 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.
authors.forename: Justin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, National Cancer Institute, Gaithersburg, MD 20877, USA.
authors.forename: Young K
authors.initials: YK
authors.lastname: Song
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, National Cancer Institute, Gaithersburg, MD 20877, USA.
authors.forename: Jun S
authors.initials: JS
authors.lastname: Wei
authors.affiliation: 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.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Goldenberg
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: W Clay
authors.initials: WC
authors.lastname: Gustafson
authors.affiliation: Departments of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA.
authors.forename: Sundari K
authors.initials: SK
authors.lastname: Rallapalli
authors.affiliation: Department of Neurology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Departments of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
authors.affiliation: Mouse Cancer Genetics Program, Center for Advanced Preclinical Research, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Serguei
authors.initials: S
authors.lastname: Kozlov
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.affiliation: Mouse Cancer Genetics Program, Center for Advanced Preclinical Research, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Van Dyke
authors.affiliation: 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.
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, National Cancer Institute, Gaithersburg, MD 20877, USA.
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Balmain
authors.affiliation: Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: qiwen.fan@ucsf.edu.
authors.forename: QiWen
authors.initials: Q
authors.lastname: Fan
authors.affiliation: 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.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
mesh_terms: D000818:Animals; D017209:Apoptosis; D001119:Arginase / Q000037:antagonists & inhibitors / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival; D033481:Chromosomes, Mammalian / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009447:Neuroblastoma / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D011963:Receptors, GABA-A / Q000235:genetics*; D016019:Survival Analysis; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D001119:Arginase