γ-aminobutyric acid (GABA) stimulates pancreatic cancer growth through overexpressing GABAA receptor π subunit

Akio Takehara, Masayo Hosokawa, Hidetoshi Eguchi, Hiroaki Ohigashi, Osamu Ishikawa, Yusuke Nakamura, Hidewaki Nakagawa

Research output: Contribution to journalArticle

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Abstract

γ-Aminobutyric acid (GABA) functions primarily as an inhibitory neurotransmitter in the mature central nervous system, and GABA/GABA receptors are also present in non-neural 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 π subunit (GABRP) in PDAC cells. We also found the expression of this peripheral type GABAA 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 GABAA 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 Ca2+ levels and activated the mitogen-activated 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.

Original languageEnglish
Pages (from-to)9704-9712
Number of pages9
JournalCancer Research
Volume67
Issue number20
DOIs
Publication statusPublished - Oct 15 2007

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Aminobutyrates
GABA Receptors
GABA-A Receptors
Pancreatic Neoplasms
gamma-Aminobutyric Acid
Adenocarcinoma
Growth
GABA-A Receptor Antagonists
HEK293 Cells
Extracellular Signal-Regulated MAP Kinases
Microarray Analysis
Mitogen-Activated Protein Kinases
Oligonucleotide Array Sequence Analysis
Northern Blotting
Small Interfering RNA
Reverse Transcription
Neurotransmitter Agents
Culture Media
Pancreas
Cell Survival

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Takehara, A., Hosokawa, M., Eguchi, H., Ohigashi, H., Ishikawa, O., Nakamura, Y., & Nakagawa, H. (2007). γ-aminobutyric acid (GABA) stimulates pancreatic cancer growth through overexpressing GABAA receptor π subunit. Cancer Research, 67(20), 9704-9712. https://doi.org/10.1158/0008-5472.CAN-07-2099

γ-aminobutyric acid (GABA) stimulates pancreatic cancer growth through overexpressing GABAA receptor π subunit. / Takehara, Akio; Hosokawa, Masayo; Eguchi, Hidetoshi; Ohigashi, Hiroaki; Ishikawa, Osamu; Nakamura, Yusuke; Nakagawa, Hidewaki.

In: Cancer Research, Vol. 67, No. 20, 15.10.2007, p. 9704-9712.

Research output: Contribution to journalArticle

Takehara, A, Hosokawa, M, Eguchi, H, Ohigashi, H, Ishikawa, O, Nakamura, Y & Nakagawa, H 2007, 'γ-aminobutyric acid (GABA) stimulates pancreatic cancer growth through overexpressing GABAA receptor π subunit', Cancer Research, vol. 67, no. 20, pp. 9704-9712. https://doi.org/10.1158/0008-5472.CAN-07-2099
Takehara, Akio ; Hosokawa, Masayo ; Eguchi, Hidetoshi ; Ohigashi, Hiroaki ; Ishikawa, Osamu ; Nakamura, Yusuke ; Nakagawa, Hidewaki. / γ-aminobutyric acid (GABA) stimulates pancreatic cancer growth through overexpressing GABAA receptor π subunit. In: Cancer Research. 2007 ; Vol. 67, No. 20. pp. 9704-9712.
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