Abstract
Pathways involved in the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA) have been implicated in the pathogenesis of high grade neuroendocrine (NE) neoplasms as well as neoplasms from a non-NE lineage. Using The Cancer Genome Atlas, overexpression of the GABA synthetic enzyme, glutamate decarboxylase 1 (GAD1), was found to be associated with decreased disease free-survival in prostate adenocarcinoma and decreased overall survival in clear cell renal cell carcinomas. Furthermore, GAD1 was found to be expressed in castrate-resistant prostate cancer cell lines, but not androgen-responsive cell lines. Using a novel fluorescence-coupled enzymatic microplate assay for GABA mediated through reduction of resazurin in a prostate neuroendocrine carcinoma (PNEC) cell line, acid microenvironment-induced stress increased GABA levels while alkaline microenvironment-induced stress decreased GABA through modulation of GAD1 and glutamine synthetase (GLUL) activities. Moreover, glutamine but not glucose deprivation decreased GABA through modulation of GLUL. Consistent with evidence in prokaryotic and eukaryotic organisms that GABA synthesis mediated through GAD1 may play a crucial role in surviving stress, GABA may be an important mediator of stress survival in neoplasms. These findings identify GABA synthesis and metabolism as a potentially important pathway for regulating cancer cell stress response as well as a potential target for therapeutic strategies.
Highlights
The neuroendocrine (NE) system is a diffuse network of cells distributed throughout various tissues and organs that can produce local or systemic effects on physiology through the secretion of hormones or neurotransmitters
gamma-aminobutyric acid (GABA) synthesis is enriched in high grade NE malignancies [13] and validated the presence of a functional GABA shunt in the prostate NE cancer (PNEC) cell line using a combination of gene expression profiling, metabolite and enzyme activity quantitation [13,25]
GABA is produced by glutamate decarboxylase 1 (GAD1)-mediated decarboxylation of glutamate derived from either glutamine or alpha-ketoglutarate from the tricarboxylic acid (TCA) cycle
Summary
The neuroendocrine (NE) system is a diffuse network of cells distributed throughout various tissues and organs that can produce local or systemic effects on physiology through the secretion of hormones or neurotransmitters. Some cells arise from neural crest, the majority are derived from multipotential epithelial progenitor cells [1]. Neuroendocrine (NE) carcinomas, believed to arise from the NE system, occur in virtually all anatomic locations and display a wide spectrum of phenotypic behaviors from benign to metastatic [2,3]. ‘‘classic’’ carcinoid tumors or low-grade NE carcinomas are well-differentiated, have a low mitotic index, and resemble NE cell hyperplasia [2,3], while small cell carcinomas or high grade NE carcinomas are aggressive and poorly differentiated [4,5,6,7,8,9]. High grade NE carcinomas characteristically have numerous areas of necrosis, a high mitotic index [2,3], and a poor prognosis. Conventional therapies do not improve patient survival in patients with high grade NE carcinoma [10]
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