γ-Aminobutyric Acid (GABA) Stimulates Pancreatic Cancer Growth through Overexpressing GABAA Receptor π Subunit

Abstract

Abstract;-Aminobutyric acid (GABA) functions primarily as an inhibitory neurotransmitter in the mature central nervous system, and GABA/GABA receptors are also present in nonneural tissues, including cancer, but their precise function in nonneuronal or cancerous cells has thus far been poorly defined. Through the genome-wide cDNA microarray analysis of pancreatic ductal adenocarcinoma (PDAC) cells as well as subsequent reverse transcription-PCR and Northern blot analyses, we identified the overexpression of GABA receptor P subunit (GABRP) in PDAC cells. We also found the expression of this peripheral type GABA A receptor subunit in few adult human organs. Knockdown of endogenous GABRP expression in PDAC cells by small interfering RNA attenuated PDAC cell growth, suggesting its essential role in PDAC cell viability. Notably, the addition of GABA into the cell culture medium promoted the proliferation of GABRP-expressing PDAC cells, but not GABRP-negative cells, and GABA A receptor antagonists inhibited this growth-promoting effect by GABA. The HEK293 cells constitutively expressing exogenous GABRP revealed the growth-promoting effect of GABA treatment. Furthermore, GABA treatment in GABRP-positive cells increased intracellular Ca 2+ levels and activated the mitogenactivated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) cascade. Clinical PDAC tissues contained a higher level of GABA than normal pancreas tissues due to the upregulation of glutamate decarboxylase 1 expression, suggesting their autocrine/paracrine growth-promoting effect in PDACs. These findings imply that GABA and GABRP could play important roles in PDAC development and progression, and that this pathway can be a promising molecular target for the development of new therapeutic strategies for PDAC.

GABA(A) Receptor Pi (GABRP) Stimulates Basal-like Breast Cancer Cell Migration through Activation of Extracellular-regulated Kinase 1/2 (ERK1/2)

“…In contrast, ERK1/2 is an established regulator of both cellular motility (33,39,40) and cytokeratin expression (34,41). GABA induces ERK1/2 activation in pancreatic (10) and renal cancers (21), hence we postulated that GABRP stimulates BLBC motility through ERK1/2 regulation of basal-like cytokeratin expression. Indeed, treatment with an ERK1/2 inhibitor recapitulated the decrease in migration and cytokeratin expression observed with diminished GABRP.…”

“…GABA(A) agonists can also induce ERK1/2 phosphorylation in cancer cell lines (10,21). Like calcium signaling, ERK1/2 signaling is pro-migratory (33,39,40), and importantly, regulates cytokeratin expression in non-breast cancer cell lines (34,41).…”

Metabolism of Vertebrate Amino Sugars with N-Glycolyl Groups

“…Taken together, these data indicate that glycolic acid does not serve as a precursor for Neu5Gc in CMAH-deficient human and mouse cells and that CMAH is likely the only endogenous source of Neu5Gc production in mammalian cells. However, increased levels of ␥-aminobutyric acid (GABA) have been found in various tumors (65)(66)(67)(68), an additional precursor of glycolyl-CoA. This led to the hypothesis that Neu5Gc might only be re-expressed under certain metabolic conditions found in tumors.…”

Ornithine decarboxylase and glutamate decarboxylase 65 as prognostic markers of gallbladder malignancy: A clinicopathological study in benign and malignant lesions of the gallbladder

“…Previous studies have shown that GABA stimulates the growth of a variety of types of cancer (23,24). The key enzyme for GABA synthesis is GAD which appears in two isoforms, GAD65 and GAD67, named according to their molecular weights (25).…”