Ethanol Overrides Dna Synthesis Inhibition In Response To Pahs (Tobacco Smoke Carcinogens): A Mechanistic Explanation

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA It is a well-established fact that alcohol intake with smoking presents a potential health risk to human. Mechanistic understanding in this regard is not clear. We previously reported that DNA damage by tobacco smoke carcinogens polynuclear aromatic hydrocarbons (PAHs) is responded by cells through induction of cell growth inhibition in different cell lines. Here we observed that ethanol (EtOH) treatment at physiologically relevant concentration (60 mM) increases DNA synthesis in DNA damaging carcinogen (BPDE) treated cells. BPDE treatment of cells elicits G1-S cell cycle arrest, but EtOH does not have any significant modulating effect on G1-S arrest indicating increased DNA synthesis by EtOH is due to modulation of some other signaling event(s). EtOH co-treatment/pretreatment is unable to modulate BPDE-induced p53 accumulation and p53 phosphorylation at ser15 and ser20 indicating increased DNA synthesis by EtOH is p53 independent. We also observed that EtOH co-treatment/pretreatment potentiates BPDE-induced phosphorylation and activation of ERKs only and not p38 MAPK. Interestingly, treatment of cells with MEK1 inhibitor (PD098059) significantly reduced ethanol's ability to increase DNA synthesis in BPDE treated cells. This finding indicates that the ability of EtOH to potentiate BPDE-induced ERK activation may potentiate PAH-induced tumorigenesis. Note: This abstract was not presented at the meeting. Citation Format: Jagat J. Mukherjee, Subodh Kumar. Ethanol overrides DNA synthesis inhibition in response to PAHs (tobacco smoke carcinogens): a mechanistic explanation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1581. doi:10.1158/1538-7445.AM2014-1581