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Carcinogenesis Advance Access published online on February 12, 2006
Carcinogenesis, doi:10.1093/carcin/bgi357
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received March 25, 2005
Revised January 19, 2006
Accepted January 27, 2006

CARCINOGENESIS

Ripe areca nut extract induces G1 phase arrests and senescence-associated phenotypes in normal human oral keratinocyte

Ssu-Yi Lu 1 *, Kuo-Wei Chang 2 *, Chung-Ji Liu 3, Yu-Hsin Tseng 1, Hsuan-Hsuan Lu 1, Suz-Ying Lee 1, and Shu-Chun Lin 1 *

1 Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan
2 Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan; Department of Dentistry, Taipei Veterans General Hospital, Taipei, Taiwan
3 Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan; Oral and Maxillofacial Surgery, Taipei Mackay Memorial Hospital, Taipei, Taiwan

* To whom correspondence should be addressed.
Shu-Chun Lin, E-mail: sclin{at}ym.edu.tw


  Abstract

Around 200-600 million Asians chew areca (also called betel), which contains a mixture of areca nut and other ingredients. Epidemiological evidences indicated that areca use is tightly linked to oral carcinogenesis. This study investigated the effects of ripe areca nut extract (ANE) on cultured normal human oral keratinocyte (NHOK). Acute subtoxic ANE treatment inhibited DNA synthesis and induced cell cycle arrest at G1 phase in early passage (< 4th passage) cells. This was accompanied with a slight increase in the sub-G1 cellular fraction. O(6)-methylguanine-DNA methyltransferase, Hsp27 and p38MAPK was up-regulated. p16 and p21 were remarkably up-regulated early and declined afterwards. In contrast, the increase of de-phosphorylated Rb seemed to be secondary to the episodes of p16 and p21 up-regulation. To simulate the chronic areca exposure in vivo, constant ANE treatment in serial NHOK culture was performed. It resulted in a significant decrease in the population doubling, increase in senescence-associated ß-galactosidase and decrease in cell proliferation in NHOK of late passages (≥ 4th passage). Induction of senescence-associated phenotypes, G2/M accumulation and genomic instability following long-term ANE treatment was also observed in a low grade oral carcinoma cell. ANE-treated NHOK also had a higher nuclear NF-{kappa}B fraction and a lower cytosolic I{kappa}B{alpha} level relative to the control in late passages. Moreover, electrophoretic mobility shift assay indicated that ANE treatment shifted the NF-{kappa}B complex from high mobility position to lower mobility position in late-passaged NHOK. ANE treatment also up-regulated IL-6 and COX-2 mRNA expressions in late-passaged NHOK. In summary, our findings suggest that ANE induces the cell cycle arrest at G1/S phase and the occurrence of senescence-associated phenotypes of NHOK. The up-regulation of p38MAPK, p16, p21, NF-{kappa}B, IL-6 and COX-2 are likely to participate in the control of these impacts.

Keywords: areca; cell cycle; NF-{kappa}B; oral carcinoma; p16; p21.
*These authors have equal contribution to this work
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