γ-Aminobutyric Acid as a Promoting Factor of Cancer Metastasis; Induction of Matrix Metalloproteinase Production Is Potentially Its Underlying Mechanism

Haruhito Azuma, Teruo Inamoto, Takeshi Sakamoto, Satoshi Kiyama, Takanobu Ubai, Yuko Shinohara, Kentaro Maemura, Motomu Tsuji, Naoki Segawa, Hiroshi Masuda, Kiyoshi Takahara, Yoji Katsuoka, Masahito Watanabe

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Abstract

We investigated expression of γ-aminobutyric acid (GABA), glutamate decarboxylase, and matrix metalloproteinase (MMP) in the prostates of patients with cancer or benign prostatic hypertrophy by immunohistochemical study. Marked expression of GABA, glutamate decarboxylase 67, and MMPs was observed in the prostates of cancer patients with metastasis (n = 72) and lymph node metastasis, although only sparse expression was noted in those of cancer patients without metastasis (n = 76) or patients with benign prostatic hypertrophy (n = 152). We then investigated the influence of GABA stimulation on in vitro MMP production and the invasive ability of cancer cells using human prostate cancer cell line C4-2. The production of MMPs increased significantly in cancer cells after a 24-h incubation with GABA. Cell invasion assay using a BioCoat Matrigel Invasion Chamber kit revealed that GABA stimulation significantly promoted the invasive ability of cancer cells and that addition of MMP inhibitor GM6001 significantly decreased GABA-induced migration. This may indicate the involvement of MMP activity in GABA-induced cancer cell invasion. We further analyzed the transmission pathway by performing GABA receptor modulation. The GABAB receptor agonist baclofen significantly increased MMP production as well as invasive ability. Moreover, blockade of the GABAB receptor pathway using GABAB receptor antagonist CGP 35348 significantly inhibited GABA-induced MMP production and invasive ability in cancer cells, whereas GABAA receptor modulation did not influence MMP production or the invasive ability of cancer cells. Thus, increased expression of GABA may be implicated in cancer metastasis by promoting MMP production in cancer cells, and the GABA B receptor pathway may be involved in the process.

Original languageEnglish
Pages (from-to)8090-8096
Number of pages7
JournalCancer Research
Volume63
Issue number23
Publication statusPublished - 01-12-2003

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Aminobutyrates
Matrix Metalloproteinases
gamma-Aminobutyric Acid
Neoplasm Metastasis
Neoplasms
GABA-B Receptors
Glutamate Decarboxylase
Prostatic Hyperplasia
Prostatic Neoplasms
GABA Receptors
Matrix Metalloproteinase Inhibitors
GABA-A Receptors
Prostate
Lymph Nodes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Azuma, H., Inamoto, T., Sakamoto, T., Kiyama, S., Ubai, T., Shinohara, Y., ... Watanabe, M. (2003). γ-Aminobutyric Acid as a Promoting Factor of Cancer Metastasis; Induction of Matrix Metalloproteinase Production Is Potentially Its Underlying Mechanism. Cancer Research, 63(23), 8090-8096.
Azuma, Haruhito ; Inamoto, Teruo ; Sakamoto, Takeshi ; Kiyama, Satoshi ; Ubai, Takanobu ; Shinohara, Yuko ; Maemura, Kentaro ; Tsuji, Motomu ; Segawa, Naoki ; Masuda, Hiroshi ; Takahara, Kiyoshi ; Katsuoka, Yoji ; Watanabe, Masahito. / γ-Aminobutyric Acid as a Promoting Factor of Cancer Metastasis; Induction of Matrix Metalloproteinase Production Is Potentially Its Underlying Mechanism. In: Cancer Research. 2003 ; Vol. 63, No. 23. pp. 8090-8096.
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abstract = "We investigated expression of γ-aminobutyric acid (GABA), glutamate decarboxylase, and matrix metalloproteinase (MMP) in the prostates of patients with cancer or benign prostatic hypertrophy by immunohistochemical study. Marked expression of GABA, glutamate decarboxylase 67, and MMPs was observed in the prostates of cancer patients with metastasis (n = 72) and lymph node metastasis, although only sparse expression was noted in those of cancer patients without metastasis (n = 76) or patients with benign prostatic hypertrophy (n = 152). We then investigated the influence of GABA stimulation on in vitro MMP production and the invasive ability of cancer cells using human prostate cancer cell line C4-2. The production of MMPs increased significantly in cancer cells after a 24-h incubation with GABA. Cell invasion assay using a BioCoat Matrigel Invasion Chamber kit revealed that GABA stimulation significantly promoted the invasive ability of cancer cells and that addition of MMP inhibitor GM6001 significantly decreased GABA-induced migration. This may indicate the involvement of MMP activity in GABA-induced cancer cell invasion. We further analyzed the transmission pathway by performing GABA receptor modulation. The GABAB receptor agonist baclofen significantly increased MMP production as well as invasive ability. Moreover, blockade of the GABAB receptor pathway using GABAB receptor antagonist CGP 35348 significantly inhibited GABA-induced MMP production and invasive ability in cancer cells, whereas GABAA receptor modulation did not influence MMP production or the invasive ability of cancer cells. Thus, increased expression of GABA may be implicated in cancer metastasis by promoting MMP production in cancer cells, and the GABA B receptor pathway may be involved in the process.",
author = "Haruhito Azuma and Teruo Inamoto and Takeshi Sakamoto and Satoshi Kiyama and Takanobu Ubai and Yuko Shinohara and Kentaro Maemura and Motomu Tsuji and Naoki Segawa and Hiroshi Masuda and Kiyoshi Takahara and Yoji Katsuoka and Masahito Watanabe",
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Azuma, H, Inamoto, T, Sakamoto, T, Kiyama, S, Ubai, T, Shinohara, Y, Maemura, K, Tsuji, M, Segawa, N, Masuda, H, Takahara, K, Katsuoka, Y & Watanabe, M 2003, 'γ-Aminobutyric Acid as a Promoting Factor of Cancer Metastasis; Induction of Matrix Metalloproteinase Production Is Potentially Its Underlying Mechanism', Cancer Research, vol. 63, no. 23, pp. 8090-8096.

γ-Aminobutyric Acid as a Promoting Factor of Cancer Metastasis; Induction of Matrix Metalloproteinase Production Is Potentially Its Underlying Mechanism. / Azuma, Haruhito; Inamoto, Teruo; Sakamoto, Takeshi; Kiyama, Satoshi; Ubai, Takanobu; Shinohara, Yuko; Maemura, Kentaro; Tsuji, Motomu; Segawa, Naoki; Masuda, Hiroshi; Takahara, Kiyoshi; Katsuoka, Yoji; Watanabe, Masahito.

In: Cancer Research, Vol. 63, No. 23, 01.12.2003, p. 8090-8096.

Research output: Contribution to journal › Article

TY - JOUR

T1 - γ-Aminobutyric Acid as a Promoting Factor of Cancer Metastasis; Induction of Matrix Metalloproteinase Production Is Potentially Its Underlying Mechanism

AU - Azuma, Haruhito

AU - Inamoto, Teruo

AU - Sakamoto, Takeshi

AU - Kiyama, Satoshi

AU - Ubai, Takanobu

AU - Shinohara, Yuko

AU - Maemura, Kentaro

AU - Tsuji, Motomu

AU - Segawa, Naoki

AU - Masuda, Hiroshi

AU - Takahara, Kiyoshi

AU - Katsuoka, Yoji

AU - Watanabe, Masahito

PY - 2003/12/1

Y1 - 2003/12/1

N2 - We investigated expression of γ-aminobutyric acid (GABA), glutamate decarboxylase, and matrix metalloproteinase (MMP) in the prostates of patients with cancer or benign prostatic hypertrophy by immunohistochemical study. Marked expression of GABA, glutamate decarboxylase 67, and MMPs was observed in the prostates of cancer patients with metastasis (n = 72) and lymph node metastasis, although only sparse expression was noted in those of cancer patients without metastasis (n = 76) or patients with benign prostatic hypertrophy (n = 152). We then investigated the influence of GABA stimulation on in vitro MMP production and the invasive ability of cancer cells using human prostate cancer cell line C4-2. The production of MMPs increased significantly in cancer cells after a 24-h incubation with GABA. Cell invasion assay using a BioCoat Matrigel Invasion Chamber kit revealed that GABA stimulation significantly promoted the invasive ability of cancer cells and that addition of MMP inhibitor GM6001 significantly decreased GABA-induced migration. This may indicate the involvement of MMP activity in GABA-induced cancer cell invasion. We further analyzed the transmission pathway by performing GABA receptor modulation. The GABAB receptor agonist baclofen significantly increased MMP production as well as invasive ability. Moreover, blockade of the GABAB receptor pathway using GABAB receptor antagonist CGP 35348 significantly inhibited GABA-induced MMP production and invasive ability in cancer cells, whereas GABAA receptor modulation did not influence MMP production or the invasive ability of cancer cells. Thus, increased expression of GABA may be implicated in cancer metastasis by promoting MMP production in cancer cells, and the GABA B receptor pathway may be involved in the process.

AB - We investigated expression of γ-aminobutyric acid (GABA), glutamate decarboxylase, and matrix metalloproteinase (MMP) in the prostates of patients with cancer or benign prostatic hypertrophy by immunohistochemical study. Marked expression of GABA, glutamate decarboxylase 67, and MMPs was observed in the prostates of cancer patients with metastasis (n = 72) and lymph node metastasis, although only sparse expression was noted in those of cancer patients without metastasis (n = 76) or patients with benign prostatic hypertrophy (n = 152). We then investigated the influence of GABA stimulation on in vitro MMP production and the invasive ability of cancer cells using human prostate cancer cell line C4-2. The production of MMPs increased significantly in cancer cells after a 24-h incubation with GABA. Cell invasion assay using a BioCoat Matrigel Invasion Chamber kit revealed that GABA stimulation significantly promoted the invasive ability of cancer cells and that addition of MMP inhibitor GM6001 significantly decreased GABA-induced migration. This may indicate the involvement of MMP activity in GABA-induced cancer cell invasion. We further analyzed the transmission pathway by performing GABA receptor modulation. The GABAB receptor agonist baclofen significantly increased MMP production as well as invasive ability. Moreover, blockade of the GABAB receptor pathway using GABAB receptor antagonist CGP 35348 significantly inhibited GABA-induced MMP production and invasive ability in cancer cells, whereas GABAA receptor modulation did not influence MMP production or the invasive ability of cancer cells. Thus, increased expression of GABA may be implicated in cancer metastasis by promoting MMP production in cancer cells, and the GABA B receptor pathway may be involved in the process.

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Azuma H, Inamoto T, Sakamoto T, Kiyama S, Ubai T, Shinohara Y et al. γ-Aminobutyric Acid as a Promoting Factor of Cancer Metastasis; Induction of Matrix Metalloproteinase Production Is Potentially Its Underlying Mechanism. Cancer Research. 2003 Dec 1;63(23):8090-8096.

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