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.