Does nicotine inhibit anticancer activities of Vitamin A?
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: Lung cancer is the leading cause of cancer deaths in the United States. About 150,000 deaths each year are due to this disease, which represents about one third of all cancer deaths in the United States. It is estimated that 90% of lung cancer cases can be traced to cigarette smoking. Despite advances in lung cancer treatment by surgery, radiation, and chemo-therapy, death from lung cancer remains high. Therefore, more effective agents to prevent and treat lung cancer are urgently needed.
 
 
 
 
 
 Epidemiological and animal studies have demonstrated that vitamin A and its natural and synthetic derivatives are effective agents in preventing the development of lung cancer. Unfortunately, clinical trials of vitamin A or its derivatives did not show benefits on preventing lung cancer in cigarette smokers. We hypo-thesize that components in tobacco may inhibit the beneficial effects of vitamin A. In support of this hypothesis, we have recently observed that the anticancer activities of vitamin A are lost in a majority of human lung cancer cell lines due to lack or abnormally low levels of a cellular vitamin A receptor (RARb) that is required for the anticancer activity of vitamin A. In addition, we discovered that levels of RARb are dependent on relative amounts of two cellular proteins called nur77 and COUP-TF. Our study further showed that elevated levels of nur77 are responsible for loss of vitamin A activity, whereas high levels of COUP-TF are required for vitamin A and its derivatives to achieve their anticancer effects. Recently we observed that nicotine could decrease the anti-cancer activities of vitamin A and its derivatives. Interestingly, we found that nicotine could enhance levels of nur77 in lung cancer cells. These observations suggest that nicotine may inhibit vitamin A activities by increasing nur77 levels. 
 
 
 
 
 
 In the present study, we plan to investigate the inhibitory effect of nicotine on vitamin A activity and test the possibility of suppressing the effects of nicotine. We will first study to what degree nicotine inhibits the anticancer activity of vitamin A and its derivatives in a number of human lung cancer and normal human lung cell lines. The effect of nicotine will be evaluated alone or in combination with other cancer-promoting agents. The anticancer effects of vitamin A to be investigated include growth inhibition and causation of cell death in lung cancer cells. We will then investigate the mechanism by which nicotine increases levels of nur77 production in lung cancer. In addition, we will investigate the mechanism by which levels of COUP-TF are rendered low in lung cancer cells, so that we can test if the induction of COUP-TF could counteract nur77 activity. In order to develop more effective and specific new vitamin A derivatives, we plan to determine how nur77 functions to cause these effects. Results from these studies will contribute to our understanding of the mechanism of vitamin A inactivation caused by cigarette smoking, and may provide means to increase vitamin A activity in lung cancer cells, thereby enhancing the anti-cancer efficacy and spectrum of vitamin A and its derivatives against tobacco-associated diseases. Moreover, our results may provide a molecular basis to develop more effective vitamin A derivatives for preventing and treating tobacco-associated diseases. Results from these studies may also provide a better basis for using nicotine-replacement therapy for smoking cessation.