title: Phenolic fraction of tobacco smoke inhibits BPDE-induced apoptosis response and potentiates cell transformation: role of attenuation of p53 response.
abstract: Polynuclear aromatic hydrocarbons (PAHs) present in tobacco smoke are regarded as chemical carcinogens. Previously, we observed that a weakly acidic phenolic fraction of tobacco smoke condensate (TSCPhFr), which is devoid of PAHs, significantly potentiates (±)-anti-BP-7,8-diol-9,10-epoxide (BPDE)-induced anchorage-independent cell growth of promotion-sensitive JB6 cell, indicating its tumor-promoting potential. In the present article, we report that further fractionation of phenolic components from TSCPhFr did not show any significant potentiation of BPDE-induced cell transformation by any of the HPLC-purified phenolic fractions, indicating several phenolic components as a whole are needed for observed activity. Although the tumor-promoting activity of weakly acidic phenolic fraction of tobacco smoke had been indicated long before, no studies have been pursued to understand the mechanism(s) underlying the tumor-promoting activity of TSCPhFr. We observed that BPDE, an ultimate carcinogenic metabolite of tobacco smoke carcinogen benzo[a]pyrene, elicits apoptosis induction, which is significantly inhibited by TSCPhFr. Increased cell transformation and decreased apoptosis by TSCPhFr were associated with attenuation of BPDE-induced p53 accumulation. JB6 cells transfected with p53 siRNA showed significantly less apoptosis induction by BPDE as compared to control cells. In p53 impaired cells (which are observed to have a faster growth rate as compared to normal cells), TSCPhFr has a practically negligible effect on apoptosis induction in response to BPDE. Also, in p53 null HCT116 p53(-/-) cells, BPDE-induced apoptosis is unresponsive to TSCPhFr. Inhibition of BPDE-induced NF-κB activation was also observed by us previously. Interestingly, treatment of cells with NF-κB-specific inhibitor IKK-NBD peptide showed no effect on BPDE-induced apoptosis, whereas TSCPhFr showed moderate inhibition of apoptosis in NF-κB inhibited cells as compared to control cells. Our observations indicate that attenuation of BPDE-induced p53 response has a role in apoptosis inhibition and increased cell transformation by TSCPhFr. 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 has a role in apoptosis induction, the role of NF-κB in TSCPhFr-mediated potentiation of PAH-induced cell transformation is not clear from our studies.
authors.affiliation: Environmental Toxicology and Chemistry Laboratory, Great Lakes Center, State University of New York College at Buffalo, United States. jjmukher@buffalostate.edu
authors.forename: Jagat J
authors.initials: JJ
authors.lastname: Mukherjee
authors.forename: Subodh
authors.initials: S
authors.lastname: Kumar
authors.forename: Ronald
authors.initials: R
authors.lastname: Gocinski
authors.forename: Jacquan
authors.initials: J
authors.lastname: Williams
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced*; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D012906:Smoke / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D016328:NF-kappa B; D010636:Phenols; D012906:Smoke; D016159:Tumor Suppressor Protein p53; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide