Vitamin A derivatives as antagonists of nicotine effects
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Tobacco consumption is a major risk factor of developing lung cancer, the leading cause of death from cancer among both men and women in California. Standard surgery, radiotherapy, and chemotherapy have not resulted in a reduction of morbidity and mortality, or an improvement of quality of life of lung cancer patients. New approaches are therefore urgently needed. This endeavor, however, depends largely on our improved knowledge of the molecular basis of tobacco consumption on lung cancer growth. We recently discovered that nicotine exerts mitogenic effect in lung cancer cells by inducing the expression of TR3 (also called nur77 or NGFI-B), an orphan member of the steroid/thyroid/retinoid receptor superfamily. Paradoxically, TR3 induction is also required for apoptosis of lung cancer cells by migrating from the nucleus to mitochondria, where it interacts with Bcl-2 to initiate apoptosis. These exciting observations offer new approaches to develop novel agents for suppressing the mitogenic effect of nicotine and for inducing apoptosis of lung cancer cells. In searching for such agents, we have observed that the translocation of TR3 from the nucleus to mitochondria requires retinoid X receptor (RXR), a receptor for a class of specific vitamin A derivatives. Moreover, we have identified several new vitamin A derivatives (RXR ligands) capable of inducing RXR nuclear export (referred as rexporters). Based on these results, we hypothesize that rexporters can antagonize the mitogenic effects of nicotine and induce apoptosis of lung cancer cells by inducing TR3 nuclear export and mitochondrial targeting. In this multidisciplinary Research Project application, we propose to study whether rexporters suppress the mitogenic effect of nicotine in lung cancer cells and the underlying molecular mechanisms, with the goals of identifying more effective and specific rexporters for lung cancer therapy. Five aims are proposed to accomplish our goals: (1). To determine the antagonistic effects of rexporters on the mitogenic activity of nicotine in lung cancer cells. (2). To investigate the mechanisms by which rexporters suppress the mitogenic effect of nicotine by inducing TR3 nuclear export. (3). To determine whether rexporters promote lung cancer cell apoptosis by inducing RXRa/TR3 mitochondrial localization. (4). To design and synthesize more effective and selective rexporters. (5) To evaluate rexporters in vitro and in vivo. Results from these studies will establish a novel mechanism for suppressing the mitogenic effect of nicotine and inducing tobacco-associated lung cancer cell apoptosis and may generate novel therapeutic agents against lung cancer. Our proposed studies are highly relevant to the goals of TRDRP by addressing important issues regarding molecular controls of the effect of nicotine on lung tumor development and have significant impact on developing more effective agents for tobacco-associated lung cancer prevention and treatment.