Epidemiological studies indicate that ethanol under certain conditions may function as co-carcinogen or tumor promoter. There is considerable evidence that alcohol abuse associated with smoking increases carcinogenic potential of tobacco smoke. The mechanism of potentiation of tobacco smoke-induced carcinogenicity by alcohol is not known. We observed that treatment of promotion sensitive JB6 Cl41 cells with (+/-)-anti- benzo[a]pyrene-7,8-diol-9,10-epoxide [anti-BPDE also called BPDE], an ultimate carcinogenic metabolite of benzopyrene (a carcinogenic PAH present in tobacco smoke) elicites DNA synthesis inhibition;and pre-treatment of cells with physiological concentration of ethanol relieves BPDE-induced DNA synthesis inhibition. Ethanol treatment does not have any effect on BPDE-DNA adduct formation which elicits cellular responses to BPDE. Previously we observed accumulation of p53 tumor suppressor protein and G1->S cell cycle arrest as well as cell transformation in response to BPDE treatment of JB6 cells. We hypothesize that one of the mechanisms of the potentiation of PAH-induced carcinogenicity by ethanol includes its ability to override DNA damage- induced cell cycle arrest via p53-dependent or p53-independent pathway and/or potentiation of cell survival through inhibition of apoptosis. Our studies in this proposal include examination of the effect of ethanol on BPDE-induced (1) anchorage- independent cell growth (in vitro measurement of potentiation of BPDE-induced cell transformation) and cell cycle profile, (2) p53 transactivating function (including stability/phosphorylation and activation) which leads to cell cycle arrest, as well as p53- independent (PI3-K/ ERK/c-Jun/AP-1 signaling) cell cycle arrest and (3) apoptosis response. Our studies will include in vitro study using promotion-sensitive mouse epidermal JB6 cells (widely used for tumor promotion studies) and human small airway epithelial (SAE) cells (relevant cell line for the study of tobacco smoke carcinogenesis). The overall objective of the proposal is to understand the underlying mechanism by which ethanol elicits its co-genotoxic effect with BPDE and thereby enhances PAH- induced carcinogenicity. Data obtained from these studies will help assessing the associated health risk presented by alcohol in presence of tobacco smoke constituents and will be useful to develop therapeutic strategies in the prevention of cancer.
The findings obtained from studies undertaken in the project will open avenues for further detailed investigations of the mechanism of potentiation of PAH-initiated carcinogenesis by alcohol, which will be useful not only for assessing the health risk presented by alcohol and tobacco smoke together but also for developing therapeutic strategies in the prevention of cancer.