Galanin receptor 2 utilizes distinct signaling pathways to suppress cell proliferation and induce apoptosis in HNSCC
Galanin receptor 2 utilizes distinct signaling pathways to suppress cell proliferation and induce apoptosis in HNSCC
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DOI：
10.3892/mmr.2014.2362
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发表时间：
2014-09-01
影响因子：
3.4
通讯作者：
Ichimura, Keiichi
中科院分区：
文献类型：
--
作者：
Kanazawa, Takeharu;Misawa, Kiyoshi;Ichimura, Keiichi
甘丙肽及其受体GALR 1和GALR 2是肿瘤抑制因子，代表头颈部鳞状细胞癌（HNSCC）的治疗靶点。在本研究中，证明了GALR 1和GALR 2阴性HNSCC细胞中GALR 1的再表达抑制肿瘤细胞增殖。这是通过细胞外调节蛋白激酶-1/2（ERK 1/2）依赖性作用于细胞周期蛋白依赖性激酶抑制剂（CKI）和细胞周期蛋白D1介导的。与甘丙肽结合，GALR 2还通过增加CKI和降低细胞周期蛋白D1水平来抑制增殖。与GALR 1相反，GALR 2的过表达也诱导caspase-3依赖性凋亡。在GALR 2转染的细胞中，甘丙肽诱导ERK 1/2的活化并抑制细胞增殖。甘丙肽刺激还降低了GALR 2转染细胞中细胞周期蛋白D1的表达，并诱导凋亡DNA梯状条带形成。用ERK 1/2特异性抑制剂U 0126和百日咳毒素预处理可阻止细胞周期蛋白D1表达的抑制，但不影响DNA梯状条带的形成。总之，在甘丙肽存在下GALR 2表达通过细胞周期阻滞和凋亡途径发挥抗肿瘤作用，并且这些途径的重新激活可能在HNSCC中具有治疗益处。
Galanin and its receptors, GALR1 and GALR2, are tumor suppressors and represent therapeutic targets in head and neck squamous cell carcinoma (HNSCC). In the present study, it was demonstrated that the re-expression of GALR1 in GALR1 and GALR2-negative HNSCC cells suppresses tumor cell proliferation. This is mediated via extracellular-regulated protein kinase-1/2 (ERK1/2)-dependent effects on the cyclin-dependent kinase inhibitors (CKI) and cyclin D1. In combination with galanin, GALR2 also suppressed proliferation by increasing CKI and decreasing cyclin D1 levels. In contrast to GALR1, overexpression of GALR2 also induced caspase-3-dependent apoptosis. It was identified that in GALR2-transfected cells, galanin induced activation of ERK1/2 and suppressed cell proliferation. Galanin stimulation also decreased the expression of cyclin D1 and induced apoptotic DNA ladder formation in GALR2-transfected cells. Pretreatment with the ERK1/2-specific inhibitor U0126 and pertussis toxin prevented the suppression of cyclin D1 expression, however did not affect DNA ladder formation. In conclusion, GALR2 expression in the presence of galanin exerts antitumor effects via cell cycle arrest and apoptotic pathways, and reactivation of these pathways may have therapeutic benefits in HNSCC..