Abstract
Abstract
With an estimated 220,800 new cases and 27,450 deaths in 2015, prostate cancer (PCa) continues to be the second leading cause of cancer related deaths in men in the US alone. Accumulation and turnover of extracellular matrix (ECM) is a hallmark of tissue injury, repair and remodeling in human diseases including PCa. Hyaluronan (HA), an extracellular glycosaminoglycan, is a major component of the ECM and plays an important role in regulating reepithelization, tissue healing and wound repair. Elevated HA levels have been shown to be associated with aggressiveness and disease progression in certain cancer types including PCa. Biological responses triggered by HA mainly depend on the HA polymer length. High molecular mass (HMM)-HA represses mitogenic signaling and has anti-inflammatory properties while low molecular mass (LMM)-HA is pro-angiogenic and promotes proliferation and inflammation. Diet-derived agents, such as flavonoids, are of particular interest for cancer chemoprevention as they offer a relatively favorable safety profile. Using HPLC-MS analysis, we identified HA as a novel target of the dietary flavonoid fisetin in tumor xenografts of human PCa NB11 and NB26 cells. Fisetin treatment decreased HA levels in PCa cells both in-vitro (40μM:40h) and in-vivo (1mg/animal). We then evaluated the effect of intraperitoneal administration of fisetin on HA size accumulation and prostate carcinogenesis using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Using the combination of Size Exclusion Chromatography (SEC) with Multi-Angle Laser Light Scattering (MALS) analysis that overcomes limitations of column calibration, we evaluated intracellular and extracellular molar mass distribution of HA in fisetin treated cell culture and animal models. We observed lower levels of HMM-HA and higher levels of pro-angiogenic LMW-HA fragments in human PCa PC3 cells. In contrast, we found that fisetin treatment increased HMM-HA and reduced LMM-HA levels in PCa cells. Remarkably, the HA size profile of fisetin treated cells resembled those of normal RWPE1 cells, which predominantly exhibited higher abundance of anti-angiogenic HMM-HA and no detectable LMW-HA. Likewise, secreted HA in fisetin treated PCa cells comprised predominantly of LMM-HA, suggesting greater accumulation of anti-angiogenic HMM-HA within the cells. Molar mass analysis of fisetin treated TRAMP tumor tissues showed an abundance of HMM-HA and reduced levels of LMM-HA when compared to untreated controls. Similarly, secreted HA in fisetin treated TRAMP animals exhibited increased pool of pro-angiogenic LMM-HA, suggesting greater accumulation of anti-angiogenic HMM-HA within the tissues. Our findings suggest that fisetin confers resistance to PCa oncogenesis by increasing the abundance of anti-angiogenic HMM-HA which is associated with delayed disease progression.
Citation Format: Rahul K. Lall, Deeba N. Syed, Mohammad Imran Khan, Vaqar M. Adhami, Yuansheng Gong, John A. Lucey, Hasan Mukhtar. Dietary flavonoid fisetin increases abundance of high-molecular-mass hyaluronan conferring resistance to prostate oncogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2615.