Abstract LB-168: Differential response to genistein on prostate cancer cells expressing different MnSOD variants

Abstract

Abstract Soy consumption may prevent prostate cancer (PCa) and be beneficial for patients with this malignancy. However, there are contradictory data on the anticancer effects of the soy isoflavone genistein, which has antioxidant properties and can affect cell proliferation and apoptosis of cancer cells through multiple mechanisms, including estrogen receptor-β mediation. Genistein also affects the expression of the manganese superoxide dismutase (MnSOD) gene and polymorphisms in this gene are related to risk of PCa. This study addressed the hypothesis that the effects of physiological concentrations of genistein on PCa cell proliferation and apoptosis are dependent on their MnSOD genotype and ER-β status, as well as on oxidative stress levels. In addition, we determined the effects of genistein on PCa cell proliferation and apoptosis at varying input levels of reactive oxygen species (O2.-), while controlling ER-β status and MnSOD genotype. PC-3 PCa cells transfected with different MnSOD genotypes (Ala/Ala and Val/Val) were cultured and treated with genistein at physiological concentrations (0, 0.01, 0.1, 0.5, 1, 5, 10 and 50 μM). After 24, 48 and 72 hours of incubation, we determined cytotoxicity, cell proliferation, apoptosis, and ER-β expression. Cell proliferation was induced at 0,5 μM genistein in PC-3 cells with MnSOD Val genotype and decreased at 2.5 μM in Ala genotype cells at 48 hours of treatment, which suggests 30-40% lower activity of Val genotype cells compared with the Ala variant, possibly increasing susceptibility to oxidative stress. ER-β expression levels were elevated by 48 hours of genistein treatment at 0.5 μM in Val genotype cells and were decreased at 2.5 μM in Ala cells. PARP protein expression levels, determined to investigate genistein’s effect on apoptosis in these cells, started to increase at 0.5 μM in Val cells and to decrease at 2.5 μM in Ala cells. These results suggest that PC-3 cells with Val genotype have increased oxidative stress and genistein at 0.5 μM induced proliferation in these cells. By contrast, genistein decreased proliferation of PC-3 cells with Ala genotype which have higher detoxification activity of superoxide radicals. Thus, genistein causes differential responses of cells with MnSOD variants, ER-β expression, and oxidative stress potential. This study help to understand the mechanisms of genistein's effects on PCa cells under physiological conditions and assess the impact of interactions of MnSOD genotype, ER-β presence, and ROS environment in the context of non-linear dose-response relationships contrasting potential benefit with possible harm of genistein. The results of this study may have important implications for PCa patients who consume soy in therapeutic and chemopreventive settings. Citation Format: Sule Terzioglu Usak, Maarten C. Bosland, Nur Özten Kandas. Differential response to genistein on prostate cancer cells expressing different MnSOD variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-168. doi:10.1158/1538-7445.AM2017-LB-168