Vitamin A depletion induced by cigarette smoke is associated with an increase in lung cancer-related markers in rats

Background: We have previously demonstrated that cigarette smoke is associated with a significant reduction of retinoic acid in rat lungs and the formation of tracheal precancerous lesions. However, the underlying mechanism of cancer risk induced by vitamin A deficiency is unclear. The purpose of this study was to determine whether the cigarette smoke-induced depletion of vitamin A is related to changes in lung cancer risk-related molecular markers. Results: We investigated the roles of the retinoic acid receptors (RARs) as well as other biomarkers for potential cancer risk in the lungs of rats exposed to cigarette smoke. Twenty-four male weanling rats were fed a purified diet and divided equally into four groups. Three experimental groups were exposed to increasing doses of cigarette smoke from 20, 40 or 60 commercial cigarettes/day for 5 days/week. After 6 weeks, the retinoic acid concentrations in the lung tissue as measured via high performance liquid chromatography (HPLC) significantly decreased (P < 0.01) in cigarette smoke exposed groups. Western Blot analysis revealed that cigarette smoke exposure increased lung protein expression of RAR alpha in a threshold manner and decreased RAR beta and RAR gamma expression in a dose-dependent fashion. Protein expressions of cyclin E and proliferating cell nuclear antigen (PCNA) were increased significantly in a dose-dependent manner in cigarette smoke exposed-groups. Additionally, there was a significant increase in protein expression of cJun and cyclin D1 demonstrating a threshold effect similar to that exhibited by RAR alpha, suggesting a potential independent signaling pathway for RAR alpha in lung carcinogenesis. Conclusions: Findings from this study suggest that cigarette smoke-induced lung retinoic acid depletion may involve two independent pathways, RAR alpha- and RAR beta-mediated, responsible for the increased cancer risk associated with cigarette smoke-induced vitamin A deficiency.