Arecoline arrests cells at prometaphase by deregulating mitotic spindle assembly and spindle assembly checkpoint: implication for carcinogenesis.
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.
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Yu-Chu
YC
Wang
Yi-Shan
YS
Tsai
Jau-Ling
JL
Huang
Ka-Wo
KW
Lee
Ching-Chuan
CC
Kuo
Chung-Sheng
CS
Wang
A-Mei
AM
Huang
Jang-Yang
JY
Chang
Yuh-Jyh
YJ
Jong
Chang-Shen
CS
Lin
D001114:Areca / Q000737:chemistry*; D001115:Arecoline / Q000009:adverse effects / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D042822:Genomic Instability / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D009062:Mouth Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D049468:Prometaphase / Q000187:drug effects* / Q000235:genetics; D008941:Spindle Apparatus / Q000187:drug effects* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors
D002273:Carcinogens; D006657:Histones; D016159:Tumor Suppressor Protein p53; D001115:Arecoline