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Does nicotine inhibit anticancer activities of Vitamin A?

Institution: The Burnham Institute for Medical Research
Investigator(s): Xiao-Kun Zhang, Ph.D.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0168 Award: $788,808
Subject Area: Cancer
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
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.

Final Report
Nicotine suppresses vitamin A activity by inhibiting RAR expression.

Epidemiological and animal studies have demonstrated that vitamin A and its natural and synthetic derivatives (retinoids) are effective agents in preventing the development of lung cancer. Unfortunately, clinical trials of retinoids on cigarette smokers have found lack of efficacy in preventing lung cancer, suggesting that cigarette smoking might impair retinoid activities. The overall objective of our project is to study the mechanism by which nicotine inhibits the anti-cancer activities of vitamin A.

Previously, we showed that nicotine could suppress anti-cancer activities of retinoids in lung cancer cells. We also found that the suppressive effect of nicotine is likely due to induction of nur77 by nicotine. In this study, we analyzed whether nur77 could regulate expression of retinoic acid receptor-beta (RAR), which is known to mediate the anti-cancer effect of retinoids.

Expression of RAR is highly induced by retinoic acid (RA) through a RA response element (RARE) that is activated by heterodimers of RARs and retinoid X receptors (RXRs). However, RAR induction is often lost in cancer cells despite expression of RARs and RXRs. In the present study, we observed that orphan receptor COUP-TF is required for RA to induce RAR expression, growth inhibition, and apoptosis in cancer cells. Expression of COUP-TF correlates with RAR induction in a variety of cancer cell lines. In addition, stable expression of COUP-TF in COUP-TF-negative cancer cells restores induction of RAR expression, growth inhibition, and apoptosis by RA, whereas inhibition of COUP-TF by expression of COUP-TF anti-sense RNA represses the RA effects. In transient transfection assay, COUP-TF strongly induced transcriptional activity of the RAR promoter in a RA- and RAR-dependent manner. The effect of COUP-TF requires both a DR-8 element that binds strongly with COUP-TF and the RARE in the RAR promoter. Mutations that either abolished COUP-TF binding to the DR-8 element or RAR binding to the RARE impaired RA- and RAR- dependent transactivation function of COUP-TF. By GST-pull-down assay, we observed that COUP-TF, through its interaction with RAR, strongly enhanced interaction of RAR with its co-activator CBP, suggesting that COUP-TF functions as an accessory protein for RAR to induce RAR promoter transcription. These results demonstrate that COUP-TF, by serving as an accessory protein for RAR to induce RAR expression, plays a critical role in regulating anti-cancer activities of retinoids. We previously showed that nur77 could physically interact with COUP-TF. We, therefore, investigated effect of nur77 on transactivation function of COUP-TF in the RAR promoter. Our results demonstrated that nur77 could strongly interfere with COUP-TF activity in various cell types examined. Together, our results demonstrate that nur77 could inhibit expression of RAR through its interaction with COUP-TF and suggest that nicotine may suppress anti-cancer effect of retinoids in part through its ability to interfere with RAR expression. (supported by a funding from TRDRP, University of California)
Publications

Induction of apoptosis by retinoids in human lung cancer cell lines
Periodical: International Journal of Cancer Index Medicus:
Authors: Li Y, Dawson MI, Lee MO, Jong L, Hobbs PD, Zhang XK ART
Yr: 1998 Vol: 75 Nbr: Abs: Pg: 88-95

Molecular determinants of AHPN (CD437)-induced growth arrest and apoptosis in human lung cancer cell lines
Periodical: Molecular and Cellular Biology Index Medicus:
Authors: Li Y, Lin B, Agadir A, Liu R, Dawson MI, Reed JC, Zhang XK ART
Yr: 1998 Vol: 18 Nbr: Abs: Pg: 4719-4731

Interaction of BAG-1 with retinoic acid receptor and its inhibition of retinoic acid-induced apoptosis in cancer cells
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Liu R, Takayama S, Zheng Y, et al ART
Yr: 1998 Vol: 273 Nbr: Abs: Pg: 16985-16992

Inhibition of trans-RA-resistant human breast cancer cell growth by retinoid X-receptor-selective retinoids
Periodical: Molecular and Cellular Biology Index Medicus:
Authors: Wu Q, Cheng Y, Dawson MI, Hobbs PD, Li Y, Zhang XK ART
Yr: 1997 Vol: 17 Nbr: Abs: Pg: 6598-6608

Activation of three distinct RXR/RAR heterodimers induces growth arrest and differentiation of neuroblastoma cells
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Giannini G, Dawson MI, Zhang XK, Thiele CJ ART
Yr: 1997 Vol: 272 Nbr: Abs: Pg: 26693-26701

Conformationally defined retinoic acid analogs: 4 potential new agents for acute promyelocytic and juvenile myelomonocytic leukemias
Periodical: Journal of Medicinal Chemistry Index Medicus:
Authors: Muccio DD, Brouillette WJ, Breitman TR, et al ART
Yr: 1998 Vol: 41 Nbr: Abs: Pg: 1679-1687

BAG-1 binds to and inhibits the retinoic acid receptor (RAR): implications for mechanisms of retinoid resistance in cancer
Periodical: Proceedings of the American Association for Cancer Research Index Medicus:
Authors: Liu R, Zheng Y, Takayama S, et al ABS
Yr: 1998 Vol: 39 Nbr: Abs: Pg: 274

Identification of a novel class of retinoic acid receptor beta-selective retinoid antagonists and their inhibitory effects on AP-1 acitivity and retinoic acid-induced apoptosis in human breast cancer cells
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Li Y, Hashimoto Y, Agadir A, Kagechika H, Zhang H-k ART
Yr: 1999 Vol: 274 Nbr: Abs: Pg: 15360-15366

Cytochrome c release and apoptosis induced by mitochondrial targeting of nuclear orphan receptor TR3
Periodical: Science Index Medicus:
Authors: Li H, Kolluri S, Gu J, et al ART
Yr: 2000 Vol: 289 Nbr: Abs: Pg: 1159-1164

Orphan receptor COUP-TF is required for induction of RARbeta, growth inhibition and apoptosis by retinoic acid in cancer cells
Periodical: Molecular and Cellular Biology Index Medicus:
Authors: Lin B, Chen G, Ziao D, et al ART
Yr: 2000 Vol: 20 Nbr: Abs: Pg: 957-970

Unique anti-activator protein-1 activity of retinoic acid receptor beta1
Periodical: Cancer Research Index Medicus:
Authors: Lin F, Ziao D, Kolluri S, Zhang X-K ART
Yr: 2000 Vol: 60 Nbr: Abs: Pg: 3271-3280

Regulation of RARbeta expression by RAR- and RXR-selective retinoids in human lung cancer cell lines: effect on growth inhibition and apoptosis induction
Periodical: International Journal of Cancer Index Medicus:
Authors: Li Y, Dawson MI, Agadir A, et al ART
Yr: 1998 Vol: 75 Nbr: Abs: Pg: 88-95

Differential effect of retinoic acid on growth regulation by phorbol ester in human cancer cell lines
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Agadir A, Chen GQ, Bost F, Li Y, Mercola D, Zhang X-K ART
Yr: 1999 Vol: 274 Nbr: Abs: Pg: 29779-29785