Abstract 5551: Potentiation of PAH-induced cell transformation by phenolic fraction of tobacco smoke: A mechanistic insight
Authors: Mukherjee Jagat J. , Kumar Subodh 
Published: June 2012

It is reported that the known content of carcinogenic polynuclear aromatic hydrocarbons (PAHs) in the tobacco smoke condensate (TSC) alone cannot account for the observed carcinogenicity of the TSC tested on mouse skin (Orris, L. et.al., 1958. J. Natl. Cancer Inst., 21: 557-561). The phenolic fraction of TSC (TSCPhFr) which is devoid of PAHs exhibits strong tumor-promoting activity in mouse skin initiated with PAHs (Roe et. al., 1959. Brit. J. Cancer., 13: 623-633). The mechanism(s) underlying the tumor promoting effect of TSCPhFr is not known. In the present communication we report that (±)-anti-BP-7,8-diol-9,10-epoxide (BPDE), an ultimate carcinogenic metabolite of tobacco smoke carcinogen benzo[a]pyrene, elicits both apoptosis induction and cell transformation in promotion sensitive mouse epidermal JB6 cell which has been extensively used for tumor promotion studies. We observed that TSCPhFr significantly potentiates BPDE-induced cell transformation associated with decreased apoptosis response indicating its tumor promoting potential. Increased cell transformation and decreased apoptosis by TSCPhFr was associated with attenuation of BPDE-induced p53 accumulation and NF-κB activation. We examined whether attenuation of p53 and NF-κB responses by TSCPhFr has any role in this regard. Chemical inhibition of p53 in JB6 cells using known p53 inhibitor pifithrin alpha showed potentiation of BPDE-induced p53 accumulation instead of down-regulation as expected. Since pifithrin alpha's role in p53 inhibition is controversial as reported in many studies, we used genomic inhibitor (p53 siRNA) to down-regulate p53 response. We observed that either JB6 cells transfected with p53 siRNA or p53 deficient HCT116 cells (HCT116p53-/−) shows significantly less apoptosis induction and more colony formation on soft agar by BPDE compared to control cells. In p53 impaired both cell lines (which are observed to have faster growth rate compared to normal cells) TSCPhFr has practically negligible effect on apoptosis induction and soft agar colony formation in response to BPDE. Interestingly treatment of cells with IKK-NBD peptide NF-κB-specific inhibitor) has variable effects on BPDE-induced apoptosis induction and cell transformation. Our observations indicate that attenuation of BPDE-induced p53 response by TSCPhFr has a role in apoptosis inhibition and increased cell transformation. These findings have implication with regard to the underlying mechanism of tumor promoting activity of TSCPhFr in PAH-induced carcinogenesis. Although p53 mediated NF-κB activation is involved in DNA damage-induced apoptosis induction as reported by others (Nature 2000, 404:892-897), the role of NF-κB in PAH-induced apoptosis and cell transformation is not clear (supported by NCI grant 1R15CA125630).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5551. doi:10.1158/1538-7445.AM2011-5551