Abstract
Abstract
Prostate cancer (PCa) is one of the most prevalent cancers affecting males in western countries. Many therapeutic strategies are available for treatment of PCa but cancer relapses in ∼10-50% of cases. Hyaluronan (HA), an extracellular glycosaminoglycan, is primarily synthesized by HA synthase (HAS) enzymes HAS-1, -2 and -3. In the undiseased state, HA regulates several cellular functions such as reepithelization, tissue healing, wound repair and brain development. Elevated HA levels have been shown to be associated with aggressiveness and disease progression in certain cancer cell types. We observed increased levels of HA in human PCa cells compared to normal prostate epithelial cells. Prostate tissues from TRAMP, a spontaneous murine PCa progression model, exhibited gradual increase in HA levels with disease progression. Serum samples and prostate tissues from human PCa patients showed significant increase in HA levels that correlated with advance in disease stage. Notably, all PCa cell lines expressed both HAS-2 and -3 at much higher levels compared to normal prostate epithelial cells. Identifying a dietary non-toxic inhibitor at achievable concentrations that can effectively suppress HAS levels and lessens HA production can significantly improve the disease outcome. Epidemiological studies over the past decade have identified plant-based diet rich in flavonoids as an attractive option in cancer prevention and therapy. Fisetin, found in many fruits and vegetables belongs to the flavonol subgroup of flavonoids and has shown potential to be effective against PCa. Using discovery based metabolomics, we identified HA as a novel target of the dietary flavonoid fisetin. In vitro studies in MNU-6 model, a unique family of human PCa cell lines (NrPEC, RWPE, NA22, NB14, NB11 and NB26) that mimics multiple steps of prostate carcinogenesis, with fisetin treatment (40μM: 48h) decreased HA levels and inhibited cell growth and proliferation. HA interaction with its primary receptor CD44 results in activation of pSTAT3, pSrc, MMP-2, MMP-9 proteins. Fisetin treatment of tumorogenic NB11 and NB26 cells inhibited protein expression of pSTAT3, pSrc, MMP-2, and -9. To establish in-vivo relevance of these in-vitro findings, we determined HA levels in two different murine models. LC-MS/MS analysis of tumors from athymic nude mice xenografted with tumorogenic NB11 and NB26 cells showed a significant decrease in HA abundance in fisetin treated animals. Moreover, reduced HA levels in fisetin-treated TRAMP mice were associated with inhibition of PCa development and increased survival. This study establishes that fisetin is a HAS inhibitor and a potential agent for treating human PCa. Modulation of HA using fisetin may be a viable option for augmenting the current standard of care in PCa patients.
Citation Format: Rahul K. Lall, Mohammad Imran Khan, Deeba N. Syed, Vaqar M. Adhami, Hasan Mukhtar. Hyaluronan: A novel target of dietary flavonoid fisetin in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4659. doi:10.1158/1538-7445.AM2015-4659