The aryl hydrocarbon receptor is a ligand activated transcription factor which regulates biological responses to a variety of environmental pollutants, such as dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and cigarette smoke. The purpose of this study was to determine whether cigarette smoke condensate (CSC) is capable of activating the AHR in normal human oral keratinocytes (NHOK) and inhibiting their ability to senesce. Towards this end, NHOK were isolated from human subjects and were cultured in the presence or absence of either TCDD or CSC. While neither TCDD nor CSC treatments altered the lifespan of NHOK in culture, both were capable of suppressing a culture induced premature senescence as indicated by their ability to decrease the mRNA and protein levels of the senescence markers p16INK4a, p53 and p15INK4b. A role of the AHR in mediating these events is indicated by the observations that the TCDD and CSC-induced decreases in p15INK4b, p16INK4a and p53 expression was accompanied by a corresponding increase in the expression levels of the AHR target gene, CYP1A1. In addition, cotreatment with the AHR antagonist, 3′-methoxy-4′-nitroflavone (MNF) blocked the effects of TCDD and CSC on p53 and CYP1A1 expression. The findings of this study indicate that in NHOK, CSC is capable of altering a key cell fate decision, i.e., commitment to premature senescence, that is in part, dependent on the AHR. These results support the idea that progression of CSC-induced tumorigenesis may include an AHR-mediated inhibition of senescence that contributes to immortalization and agents that block the actions of the AHR may be effective components of novel cancer therapeutics.

Original languageEnglish
Pages (from-to)693-700
Number of pages8
JournalOral Oncology
Issue number7
StatePublished - Aug 2007

Bibliographical note

Funding Information:
We are thankful to Drs Stephen Safe and Thomas Gaseiwicz for providing us with TCCD and MNF. We would also like to thank all the members of the Swanson lab for providing their insights into this project and for their assistance in the preparation of this manuscript. This work was supported by NIH grants ES11295 and ES08088.


  • Aryl hydrocarbon receptor
  • Cigarette smoke condensate
  • Oral keratinocytes
  • Senescence

ASJC Scopus subject areas

  • Oral Surgery
  • Oncology
  • Cancer Research


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