Galanin and galanin receptor type 1 suppress proliferation in squamous carcinoma cells: activation of the extracellular signal regulated kinase pathway and induction of cyclin-dependent kinase inhibitors
Galanin and galanin receptor type 1 suppress proliferation in squamous carcinoma cells: activation of the extracellular signal regulated kinase pathway and induction of cyclin-dependent kinase inhibitors
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DOI：
10.1038/sj.onc.1210384
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发表时间：
2007-08-01
期刊：
影响因子：
8
通讯作者：
Carey, T. E.
中科院分区：
文献类型：
--
作者：
Kanazawa, T.;Iwashita, T.;Carey, T. E.
甘丙肽受体 1 (GALR1) 定位于头颈部鳞状细胞癌 18q 缺失的常见区域，并且经常因甲基化而失活。为了研究 GALR1 及其信号通路的影响，我们在不表达内源性 GALR1 的人口腔癌细胞系 (UM-SCC-1-GALR1) 中稳定表达血凝素标记的 GALR1。在转染的细胞中，甘丙肽诱导细胞外调节蛋白激酶-1/2 (ERK1/2) 的激活并抑制增殖。甘丙肽刺激介导细胞周期蛋白 D1 表达减少，细胞周期蛋白依赖性激酶抑制剂 (CKI)、p27 (Kip1) 和 p57 (Kip2) 表达增加。用 ERK1/2 特异性抑制剂 U0126 进行预处理可防止这些甘丙肽诱导的作用。甘丙肽处理后，UM-SCC-1-GALR1 和 UM-SCC-1-mock 细胞中磷脂酰肌醇 3-激酶 (PI3K) 通路激活没有差异。百日咳毒素和 LY294002 抑制表明甘丙肽和 GALR1 通过 God 诱导 ERK1/2 激活，而不是与 G beta gamma 亚基相关的 PI3K 途径。甘丙肽和 GALR1 还可抑制体内集落形成和肿瘤生长。我们的结果表明 GALR1（一种 Gi 蛋白偶联受体）作为肿瘤抑制基因，通过 ERK1/2 激活抑制细胞增殖。
Galanin receptor 1(GALR1) maps to a common region of 18q loss in head and neck squamous cell carcinomas and is frequently inactivated by methylation. To investigate effects of GALR1 and its signaling pathways, we stably expressed hemaglutinin-tagged GALR1 in a human oral carcinoma cell line (UM-SCC-1-GALR1) that expresses no endogenous GALR1. In transfected cells, galanin induced activation of the extracellular-regulated protein kinase-1/2 (ERK1/2) and suppressed proliferation. Galanin stimulation mediated decreased expression of cyclin D1 and increased expression of the cyclin-dependent kinase inhibitors (CKI), p27(Kip1) and p57(Kip2). Pretreatment with the ERK1/2-specitic inhibitor U0126 prevented these galanin-induced effects. Phosphatidylinositol 3-kinase (PI3K) pathway activation did not differ in UM-SCC-1-GALR1 and UM-SCC-1-mock cells after galanin treatment. Pertussis toxin and LY294002 inhibition demonstrated that galanin and GALR1 induce ERK1/2 activation via God, not the PI3K pathway-linked to the G beta gamma subunit. Galanin and GALR1 also inhibit colony formation and tumor growth in vivo. Our results implicate GALR1, a Gi protein-coupled receptor, as a tumor suppressor gene that inhibits cell proliferation via ERK1/2 activation.