Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Oral Oncol. 2010 Apr;46(4):255-62. doi: 10.1016/j.oraloncology.2010.01.003. Epub 2010 Feb 6.
One apparent feature of cancerous cells is genomic instability, which may include various types of chromosomal aberrations, such as translocation, aneuploidy, and the presence of micronuclei inside the cells. Mutagenic factors that promote the emergence of genomic instability are recognized as risk factors for the development of human malignancies. In Asia, betel quid (BQ) chewing is one of such risk factors for oral cancer. Areca nut is an essential constitute of BQ and is declared as a group I carcinogen by the International Agency for Research on Cancer. However, the molecular and cellular mechanisms regarding the carcinogenicity of areca nut are not fully explored. Here we reported that arecoline, a major alkaloid of areca nut, could arrest cells at prometaphase with large amounts of misaligned chromosomes. This prometaphase arrest was evidenced by condensed chromosome pattern, increased histone H3 phosphorylation, and accumulation of mitotic proteins, including aurora A and cyclin B(1). To investigate the molecular mechanisms accounting for arecoline-induced prometaphase arrest, we found that arecoline could stabilize mitotic spindle assembly, which led to distorted organization of mitotic spindles, misalignment of chromosomes, and up-regulation of spindle assembly checkpoint (SAC) genes. The SAC proteins BubR1 and Mps1 were differentially modified between the cells treated with arecoline and nocodazole. This together with aurora A overexpression suggested that SAC might be partly suppressed by arecoline. As a result, the arecoline-exposed cells might produce progeny that contained various chromosomal aberrations and exhibited genomic instability.
癌细胞的一个明显特征是基因组不稳定，其中可能包括各种类型的染色体异常，如易位、非整倍体和细胞内存在微核。促进基因组不稳定出现的诱变因素被认为是人类恶性肿瘤发展的危险因素。在亚洲，嚼槟榔是口腔癌的危险因素之一。槟榔是 BQ 的重要组成部分，被国际癌症研究机构宣布为一类致癌物。然而，槟榔致癌的分子和细胞机制尚未完全探索。在这里，我们报道了槟榔中的主要生物碱槟榔碱能够使大量染色体排列不齐的细胞停滞在前期。这种前期停滞的证据是染色体凝聚模式、组蛋白 H3 磷酸化增加以及有丝分裂蛋白（包括 Aurora A 和细胞周期蛋白 B1）的积累。为了研究导致槟榔碱诱导前期停滞的分子机制，我们发现槟榔碱可以稳定有丝分裂纺锤体的组装，从而导致纺锤体结构扭曲、染色体排列不齐和纺锤体组装检查点（SAC）基因的上调。与长春花碱处理的细胞相比，槟榔碱处理的细胞中的 SAC 蛋白 BubR1 和 Mps1 存在差异修饰。这与 Aurora A 的过表达一起表明，SAC 可能部分被槟榔碱抑制。结果，暴露于槟榔碱的细胞可能产生含有各种染色体异常和表现出基因组不稳定的后代。
