Gamma-aminobutyric acid as a promoting factor of cancer metastasis; induction of matrix metalloproteinase production is potentially its underlying mechanism.
Gamma-aminobutyric acid as a promoting factor of cancer metastasis; induction of matrix metalloproteinase production is potentially its underlying mechanism.
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发表时间：
2003
期刊：
影响因子：
11.2
通讯作者：
H. Azuma;T. Inamoto;Takeshi Sakamoto;S. Kiyama;T. Ubai;Y. Shinohara;K. Maemura;M. Tsuji;N. Segawa
中科院分区：
文献类型：
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作者：
H. Azuma;T. Inamoto;Takeshi Sakamoto;S. Kiyama;T. Ubai;Y. Shinohara;K. Maemura;M. Tsuji;N. Segawa
我们采用免疫组化方法研究了γ -氨基丁酸（GABA）、谷氨酸脱羧酶和基质金属蛋白酶（MMP）在前列腺癌或良性前列腺肥大患者前列腺中的表达。GABA、谷氨酸脱羧酶67和MMPs在有转移（n = 72）和淋巴结转移的癌症患者的前列腺中有显著表达，而在无转移（n = 76）和良性前列腺肥大（n = 152）的癌症患者中只有稀疏表达。然后，我们以人前列腺癌细胞C4-2为实验对象，研究了GABA刺激对体外MMP生成和癌细胞侵袭能力的影响。与GABA孵育24小时后，癌细胞中MMPs的产生显著增加。使用BioCoat Matrigel侵袭室试剂盒进行细胞侵袭实验发现，GABA刺激可显著提高癌细胞的侵袭能力，添加MMP抑制剂GM6001可显著降低GABA诱导的癌细胞迁移。这可能表明MMP活性参与了gaba诱导的癌细胞侵袭。我们通过GABA受体调节进一步分析了其传递途径。GABA(B)受体激动剂巴氯芬显著增加MMP的产生和侵袭能力。此外，使用GABA(B)受体拮抗剂CGP 35348阻断GABA(B)受体通路可显著抑制GABA诱导的MMP产生和癌细胞的侵袭能力，而GABA(A)受体调节不影响MMP产生或癌细胞的侵袭能力。因此，GABA表达的增加可能通过促进癌细胞中MMP的产生而与癌症转移有关，GABA(B)受体途径可能参与了这一过程。
We investigated expression of gamma-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 GABA(B) receptor agonist baclofen significantly increased MMP production as well as invasive ability. Moreover, blockade of the GABA(B) receptor pathway using GABA(B) receptor antagonist CGP 35348 significantly inhibited GABA-induced MMP production and invasive ability in cancer cells, whereas GABA(A) 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.