Abstract 1896: Role of reactive oxygen species in the extracellular matrix-influenced sensitivity of various prostate cancer cell lines to methylseleninic acid and selenite

Abstract

Abstract Understanding various factors that influence cancer-preventive actions of chemopreventive agents is important in order to optimize their potential to prevent cancer. Particularly, this is important for various forms of selenium which have a differential ability to prevent tumor promotion. Previously, we compared the relative selenium sensitivity of various prostate cancer cell lines with a common lineage showing progression characteristics from low to high degree of malignancy and mimicking different stages of tumor progression. In the current study, we used prostate cancer cell lines with increasing tumorigenicity and invasive ability: WPE1-NA22 showing the lowest, WPE1-NB11 and WPE1-NB14 showing intermediate, and WPE1-NB26 showing the greatest. In all these cell lines, both methylseleninic acid (MSA) and selenite induced growth inhibition and apoptosis, but all cell lines were more sensitive to selenite than MSA. These cell lines showed a variation in sensitivity to MSA and exhibited a decrease in sensitivity with an increase in tumor progression. On the contrary, no appreciable variation in the sensitivity to selenite was observed among these cell lines. Additionally, the cell lines were less susceptible to MSA-induced growth inhibition when they were grown on a surface coated with collagen. However, such differences were not observed with selenite. We measured the rate of generation of reactive oxygen species (ROS), particularly hydrogen peroxide, using 2′,7′-dichlorofluorescin diacetate in cells treated with MSA and selenite. The rate of generation of ROS was relatively higher in the MSA-sensitive cell line (WPE1-NB11), whereas it was lower in the MSA-resistant cell line. Overall, the rate of generation of ROS correlated to the relative sensitivity of these cell lines to MSA, whereas selenite did not induce an appreciable increase in ROS generation under these conditions. Furthermore, cells grown on a collagen surface showed a decrease in the rate of ROS generation. This suggested that collagen-induced prevention of MSA action might have been caused by either a low rate of generation of ROS or enhanced scavenging of ROS. This data is in agreement with our previous findings showing the reaction of methylselenol, a reduced product of methylselenol with hydrogen peroxide. MSA reacts with cysteine-rich regions in critical molecular targets, such as protein kinase C isoenzymes, and during this process, MSA is converted to a volatile methylselenol. Methylselenol is converted back to nonvolatile MSA by reacting with hydrogen peroxide. This peroxidatic redox cycle is effective in inactivating these types of targets. Contrary, selenite reacts directly with cysteine-rich regions in protein kinase C without the need for ROS. Therefore, different selenocompounds may vary in their mode of action. This study was supported by the National Cancer Institute grant CA099216. Citation Format: Rayudu Gopalakrishna, Jessica Tran, Alan Hung, Lu Tian, Karen K. Wang, William T. Zeng, Brian Lam, Usha Gundimeda. Role of reactive oxygen species in the extracellular matrix-influenced sensitivity of various prostate cancer cell lines to methylseleninic acid and selenite. [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 1896. doi:10.1158/1538-7445.AM2015-1896