Arecoline arrests cells at prometaphase by deregulating mitotic spindle assembly and spindle assembly checkpoint: Implication for carcinogenesis

Wang, Yu-Chu; Tsai, Yi-Shan; Huang, Jau-Ling; Lee, Ka-Wo; Kuo, Ching-Chuan; Wang, Chung-Sheng; Huang, A-Mei; Chang, Jang-Yang; Jong, Yuh-Jyh; Lin, Chang-Shen

doi:10.1016/j.oraloncology.2010.01.003

« Previous Next »Oral Oncology
Volume 46, Issue 4 , Pages 255-262, April 2010

Arecoline arrests cells at prometaphase by deregulating mitotic spindle assembly and spindle assembly checkpoint: Implication for carcinogenesis

Yu-Chu Wang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- These authors contributed equally to this work.
Yi-Shan Tsai
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- These authors contributed equally to this work.
Jau-Ling Huang
- Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan
Ka-Wo Lee
- Department of Otolaryngology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
Ching-Chuan Kuo
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
Chung-Sheng Wang
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
A-Mei Huang
- Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
Jang-Yang Chang
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
Yuh-Jyh Jong
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Pediatrics and Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
Chang-Shen Lin
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Corresponding author. Address: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, No. 100, Shi-Chuan 1st Rd., Kaohsiung 807, Taiwan. Tel.: +886 7 3121101 2019; fax: +886 7 3218309.

Received 6 December 2009; received in revised form 28 December 2009; accepted 4 January 2010. published online 08 February 2010.

Summary

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 B₁. 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.

Keywords: Arecoline, Betel quid, Chromosomal aberrations, Genomic instability, Mitotic arrest, Spindle assembly checkpoint