Galanin Receptor subtypes 2 as therapeutic targets in Head and Neck Squamous cell Carcinoma

甘丙肽受体亚型 2 作为头颈鳞状细胞癌的治疗靶点

• 批准号: 20592027
• 负责人: KANAZAWA Takeharu
• 金额: $ 2.91万
• 依托单位: Jichi Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20592027/
• 关键词: GALR2; G蛋白共役受容体; 癌抑制遺伝子; 頭頸部癌; G蛋白共役受; GALR1; G蛋白共役受容

Purpose : Galanin and its receptors, GALR1 and GALR2, are known as tumor suppressor and focused as therapeutic targets in head and neck squamous cell carcinoma(HNSCC). Previously, we demonstrated that the function of signaling pathways of GALR1 and GALR2.In HNSCC cells with silenced GALR1 and GALR2, we showed that reexpressed GALR1 suppresseed tumor cell proliferation via the extracellular-regulated protein kinase-1/2(ERK1/2)-mediated effects on the cyclin-dependent kinase inhibitors(CKI) and cyclinD1.On the other hands, in the GALR2-transfected HNSCC cells, galanin suppressed proliferation and induced apoptosis. Galanin stimulation also mediated decreased expression of cyclin D1 and increased expression of the CKI, p27^<Kip1> and p57^<Kip2>. These effects were similar to GALR1, but GALR2 also induced caspase-3-dependent apoptosis, which was confirmed by Annexin-V staining and DNA fragmentation analysis. Thus, we understood the function of GALR1 and GALR2 as tumor suppressor, but the s … More ignaling pathway of GALR2 is still unclear. In this study, we investigated the signaling pathway of GALR2 in HNSCC cells that have mutant p53 and do not express GALR1.Experimental Design : The HNSCC cell line with a splice site mutation causing a 46-bp p53 off-frame deletion, was stably transfected to express GALR2 and examined the expression of phospho-ERK1/2 by immunoblotting. Results : Galanin treatment of the GALR2-transfected cells caused morphologic changes and a marked decrease in cell number that were not observed in the mock transfected cells. In the GALR2-transfected cells, galanin induced activation of the extracellular-regulated protein kinase-1/2(ERK1/2) and suppresses cell proliferation, not the mock. transected cells. Galanin stimulation also mediated decreased expression of cyclin D1.Pretreatment with the ERK1/2-specific inhibitor U0126 prevented the suppression of cyclin D1 expression. Conclusion : This study shows that reexpressed GALR2 also suppresses tumor cell proliferation via the almost same pathway for GALR1.However, the ERK1/2-specific inhibitor could not prevent the GALR2 mediated apoptosis. This study suggest that GALR2 uses the different signaling pathways to induce apoptosis or cell cycle arrest, but further investigations are need to understand the GALR2 signaling pathway in detail. Less

目的：甘丙肽及其受体GALR 1和GALR 2被认为是肿瘤抑制因子，并被认为是头颈部鳞状细胞癌（HNSCC）的治疗靶点。在GALR 1和GALR 2沉默的HNSCC细胞中，我们发现GALR 1的再表达通过细胞外调节蛋白激酶1/2（extracellularregulatedproteinkinase-1/2，ERK 1/2）介导的对细胞周期蛋白依赖性激酶抑制剂（cyclin-dependent kinase inhibitors，CKI）和cyclinD 1的作用抑制肿瘤细胞增殖。甘丙肽抑制增殖并诱导凋亡。甘丙肽刺激还介导了细胞周期蛋白D1表达的降低和CKI、p27^和p57^表达的增加<Kip1><Kip2>。这些作用类似于GALR 1，但GALR 2也诱导caspase-3依赖的凋亡，这通过Annexin-V染色和DNA片段化分析证实。因此，我们了解了GALR 1和GALR 2作为肿瘤抑制因子的功能，但GALR 1和GALR 2的表达与肿瘤的发生发展有关。 ...更多信息 GALR 2的信号传导途径尚不清楚。本研究旨在研究GALR 2在p53突变而不表达GALR 1的HNSCC细胞中的信号传导途径。实验设计：将p53剪接位点突变导致46 bp的离框缺失的HNSCC细胞系稳定转染表达GALR 2，并通过免疫印迹检测磷酸化ERK 1/2的表达。结果如下：甘丙肽处理GALR 2转染的细胞引起的形态学变化和细胞数量的显着减少，没有观察到在模拟转染的细胞。在GALR 2转染的细胞中，甘丙肽诱导细胞外调节蛋白激酶-1/2（ERK 1/2）的激活并抑制细胞增殖，而不是模拟细胞。横切细胞甘丙肽刺激还介导细胞周期蛋白D1表达的降低。用ERK 1/2特异性抑制剂U 0126预处理可以阻止细胞周期蛋白D1表达的抑制。结论：本研究表明，GALR 2的再表达也通过与GALR 1几乎相同的途径抑制肿瘤细胞增殖，但ERK 1/2特异性抑制剂不能阻止GALR 2介导的凋亡。本研究提示GALR 2通过不同的信号通路诱导细胞凋亡或细胞周期阻滞，但对GALR 2信号通路的详细了解还需要进一步的研究。少

项目成果

Galanin Receptor subtypes 1 and 2 as therapeutic targets in HNSCC

甘丙肽受体亚型 1 和 2 作为 HNSCC 的治疗靶点

• 发表时间: 2010
• 期刊: Expert Opinion of Therapeutic Target
• 作者: Kanazawa;et al
• 通讯作者: et al

Galanin Receptor subtype 2 suppresses cell proliferation and…

甘丙肽受体亚型 2 抑制细胞增殖……

• 发表时间: 2009
• 期刊: Clinical Cancer Research 15
• 作者: Kanazawa;et al
• 通讯作者: et al

Galanin receptor subtype 2 suppresses cell proliferation and induces apoptosis in p53 mutant head and neck cancer cells.

• DOI: 10.1158/1078-0432.ccr-08-2443
• 发表时间: 2009-04-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Kanazawa T;Kommareddi PK;Iwashita T;Kumar B;Misawa K;Misawa Y;Jang I;Nair TS;Iino Y;Carey TE
• 通讯作者: Carey TE

GALR2 has the Different Signaling Pathway to Suppress Cell Proliferation and Induce Apoptosis in p53 Mutant Head and Neck Cancer Cells

GALR2 具有不同的信号通路来抑制 p53 突变头颈癌细胞的细胞增殖和诱导细胞凋亡

• 发表时间: 2011
• 作者: Kanazawa T;Carey TE
• 通讯作者: Carey TE