Galanin receptor subtype 2 suppresses cell proliferation and induces apoptosis in p53 mutant head and neck cancer cells.
Galanin receptor subtype 2 suppresses cell proliferation and induces apoptosis in p53 mutant head and neck cancer cells.
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DOI：
10.1158/1078-0432.ccr-08-2443
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发表时间：
2009-04-01
期刊：
影响因子：
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通讯作者：
Carey TE
中科院分区：
文献类型：
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作者：
Kanazawa T;Kommareddi PK;Iwashita T;Kumar B;Misawa K;Misawa Y;Jang I;Nair TS;Iino Y;Carey TE
甘丙肽及其三种受体（GALR 1 -3）在许多正常组织中表达，但在一些肿瘤中沉默。甘丙肽及其受体在各种肿瘤中的相互矛盾的作用已被报道。为了了解它们的功能，有必要调查各个GALR。在GALR 1和GALR 2沉默的头颈部鳞状细胞癌细胞（HNSCC）中，我们发现重新表达的GALR 1通过Erk 1/2介导的对cdk抑制剂和细胞周期蛋白D1的作用抑制肿瘤细胞增殖。其他研究表明，GALR 2可以诱导具有野生型p53的神经母细胞瘤细胞凋亡，而GALR 2刺激小细胞肺癌的增殖。在这项研究中，我们研究了GALR 2在具有突变型p53且不表达GALR 1的HNSCC细胞中的作用。UM-SCC 1是一种具有导致46-bp p53离框缺失的剪接位点突变的人口腔癌细胞系，其被稳定转染以表达GALR 2（UM-SCC-1-GALR 2）。甘丙肽处理UM-SCC-1-GALR 2引起形态学变化和细胞数量显著减少，而在UM-SCC-1-mock细胞中未观察到。甘丙肽和GALR 2导致BrdU掺入减少，p27 Kip 1和p57 Kip 2上调，以及细胞周期蛋白D1表达减少。这些作用类似于HNSCC中的GALR 1信号传导，然而，GALR 2也诱导caspase-3依赖性凋亡，这通过annexin-V染色和DNA片段化分析证实。这些在GALR 1中未观察到。该研究表明，GALR 2再表达可以抑制具有突变型p53的HNSCC细胞中的细胞增殖并诱导细胞凋亡。GALR 2可能是HNSCC治疗的一个可行靶点。
Galanin and its three receptors (GALR1-3) are expressed in many normal tissues, but silenced in some tumors. Contradictory roles for galanin and its receptors in various tumors have been reported. To understand their function, investigations of individual GALRs are necessary. In head and neck squamous carcinoma cells (HNSCC) with silenced GALR1 and GALR2, we showed that re-expressed GALR1 suppresses tumor cell proliferation via Erk1/2-mediated effects on cdk inhibitors and cyclin D1. Others showed that GALR2 could induce apoptosis in neuroblastoma cells with wild-type p53, whereas GALR2 stimulated proliferation in small cell lung cancer. In this study, we investigated the role of GALR2 in HNSCC cells that have mutant p53 and do not express GALR1. UM-SCC1, a human oral carcinoma cell line with a splice site mutation causing a 46-bp p53 off frame deletion, was stably transfected to express GALR2 (UM-SCC-1-GALR2). Galanin treatment of UM-SCC-1-GALR2 caused morphological changes and a marked decrease in cell number that were not observed in UM-SCC-1-mock cells. Galanin and GALR2 resulted in decreased BrdU incorporation, p27Kip1 and p57Kip2 up-regulation, and decreased cyclin D1 expression. These effects were similar to GALR1 signaling in HNSCC, however, GALR2 also induced caspase-3-dependent apoptosis, which was confirmed by annexin-V staining and DNA fragmentation analysis. These were not observed with GALR1. This study demonstrates that GALR2 re-expression can inhibit cell proliferation and induce apoptosis in HNSCC cells with mutant p53. GALR2 may be a feasible target for HNSCC therapy.