Abstract 3729: Resveratrol enhances the anti-proliferative response of zinc by increasing zinc-transporter protein ZIP1 in prostate cancer cells: A novel combinatorial approach for prostate cancer management

Prostate Cancer (PCa) is one of the most prevalent cancers in males across the globe. In the United States alone, 240,890 new PCa cases and 33,720 related deaths are predicted for the year 2011. Studies suggest that the essential trace element zinc is extremely important in prostate cell functions and survival. Prostate tissue can accumulate zinc at up to ten-fold higher concentration than other organs. However, the cancerous prostatic cells lose the ability to accumulate zinc and lower levels of prostatic zinc have been associated with PCa development and progression. Based on several studies, it has been suggested that lower expression of zinc transporter protein ZIP1 is associated with this neoplastic transformation and restoration of adequate zinc levels in premalignant/malignant prostate cells can abort prostate malignancy. In addition, zinc has been shown to function as an anti-proliferative agent against PCa. However, because of low ZIP1 in cancerous cells, active transport of zinc into the cells is compromised. Thus, zinc supplementation is not effective since very high concentrations of zinc are needed to achieve enough zinc inside cancerous cells. Therefore new means to enhance the bioaccumulation of sufficient zinc in the prostate tissue could be useful towards PCa management. In this study, we tested the hypothesis that grape antioxidant resveratrol will enhance zinc bioaccumulation via increasing ZIP1 in prostate, to impart a superior anti-proliferative response against PCa cells. Our data demonstrated that ZIP1 protein was markedly downregulated in human PCa tissue as compared to normal prostate tissue. Employing androgen-responsive 22Rα1 and LNCaP as well as androgen-unresponsive DU145 cell lines, we observed that a combination of resveratrol and zinc resulted in a remarkable increase in ZIP1 mRNA and protein expression in PCa cells. Further, a combination of resveratrol and zinc was found to impart a superior anti-proliferative response (inhibition of cell growth/viability and induction of apoptosis) in PCa cells, compared to either of the agent alone. Furthermore, we also found that resveratrol-zinc combination resulted in an increase in the levels of metallothioneins (MT1A, MT1X, MT2A and MT3), which play critical role in regulation of intracellular zinc levels. Taken together, our data indicate that resveratrol enhances the cellular transport of zinc via enhancing ZIP1 transporter protein and a combination of resveratrol and zinc may be a useful approach for PCa management. However, further in vivo studies are needed in appropriate animal model(s) with relevance to human disease to determine the clinical benefits of resveratrol and zinc combination against PCa. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3729. doi:1538-7445.AM2012-3729