Prostate cancer (PCa) is a major epithelial cancer among men and with the second highest incidence rate, worldwide. The high ratio of IGF-1/IGFBP-3 correlates with increased risk of many cancers including prostate cancer. In present study, we have evaluated the role of IGFBP-3 and effect of fisetin, a phytochemical, active constituent of strawberry, apple etc. in the progression of prostate cancer. The exogenous expression of IGFBP-3 moderately decreased the cell growth and it further decreased with addition of fisetin in DU145 and LNCaP cells. The restoration of IGFBP-3 in DU145 cells inhibited the clonogenic potential which is further decreased with fisetin treatment. Increased ROS content was observed in IGFBP-3 overexpression condition, however fisetin treatment reversed the ROS content in DU145, shows antioxidant behaviour. Morphological examination of mitochondria revealed that IGFBP-3 overexpression destabilizes the mitochondrial dynamics by reduction in active DRP1 level which has been reversed by fisetin treatment. We evaluated the effect on mitochondrial mass which was decreased in IGFBP-3 overexpressing DU145 cells which further decreased with addition of fisetin at 12 and 24 h. IGFBP-3 overexpression decreased the migratory potential of DU145 cells under normoxic conditions and under hypoxic condition it increased the migration of DU145 cells. Furthermore, IGFBP-3 overexpression decreased the VEGF expression as compared to vector control which can inhibit the expansion of tumor cells. Under the hypoxic conditions (1% oxygen), cells showed increased levels of IGFBP-3 when compared to normoxic conditions (21% Oxygen) in time dependent manner. The down-regulation of IGFBP-3 in PC3 cells, increased the expression of E-cadherin, a biomarker of epithelial to mesenchymal transition. The wound scratch assay showed the pro-migratory role of IGFBP-3 in PC3 cells and treatment with fisetin inhibited the migration of these cells under the hypoxic condition. The knockdown of IGFBP3 resulted in the decreased invasive potential of PC3 in comparison to cells in hypoxic state. Together with these observation, IGFBP-3 have shown biphasic character depending on normoxic and hypoxic condition in controlling the prostate cancer progression.
Citation Format: Arpit Dheeraj, Dhanir Tailor, Gagan Deep, Rana P. Singh. Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) regulates mitochondrial dynamics, EMT and angiogenesis in progression of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1095.