Abstract 3677: Prostate cancer progression decreases the cancer prevention by selenium: relation to overexpression of protein kinase Cε and selenoprotein thioredoxin reductase.

Selenium effectively prevents cancer in some cases, but fails in other cases. It could be possible that cancer-preventive actions of selenium are diminished by tumor progression, thus making this an important issue to study. In previous studies, tumor cell sensitivity to selenium was determined with commonly used, highly malignant prostate cancer cell lines such as DU145, PC-3, and LNCaP, which were originally cloned from different patients. These cell lines help us understand the mechanistic details of selenium-induced cellular effects, but due to their different genetic backgrounds, it is difficult to establish mechanisms related to cellular sensitivity to selenium. Previously, others have cloned a family of human prostate cancer cell lines with a common lineage showing progression characteristics from a low to high degree of malignancy and mimicking different stages of tumor progression seen in human prostate cancer. For this study, we used these prostate cancer cell lines with increasing tumorigenicity and invasive ability: WPE1-NA22 showing the lowest, WPE1-NB14 and WPE1-NB11 showing intermediate, and WPE1-NB26 showing the greatest. The low tumorigenic cell line, WPE1-NA22 resembles noninvasive prostatic intra-epithelial neoplasia and represents a good target for chemoprevention in humans. In this study, we found that WPE1-NA22 cells required a lower concentration of methylseleninic acid (MSA) for inhibition of cell growth (anchorage-dependent and anchorage-independent), induction of apoptosis, and inhibition of matrigel invasion. On the contrary, highly malignant cell line WPE1-NB26 required higher concentration of MSA to induce these effects, whereas moderately malignant cell lines WPE1-NB14 and WPE1-NB11 required intermediate levels of MSA. We have previously shown that protein kinase Ce (PKCe) is a molecular target for MSA and that the redox modification of this kinase is reversed by thioredoxin reductase (TR) system. Therefore, we determined whether there is an increase in expression of these two enzymes in tumor progression relating to a decrease in sensitivity to MSA. Western immunoblot analysis revealed low levels of PKCe, TR1, and TR2 in low tumorigenic WPE1-NA22 cells, while their levels were higher in advanced malignant cell lines correlating with their sensitivity to MSA. A conditional overexpression of PKCe in WPE1-NA22 cells resulted in an increase of both growth in soft agar and matrigel invasion and a decrease in sensitivity to MSA. An inhibition of TR activity in WPE1-NB26 resulted in an increase in sensitivity to MSA. Conceivably, there is an inverse correlation between the sensitivity to selenium-induced cancer prevention and prostate tumor progression involving an overexpression of PKCe and TR. Citation Format: Rayudu Gopalakrishna, Barsegh A. Barseghian, Carleen Sarksian, Jason E. Schiffman, David V. Rayudu, Usha Gundimeda. Prostate cancer progression decreases the cancer prevention by selenium: relation to overexpression of protein kinase Ce and selenoprotein thioredoxin reductase. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3677. doi:10.1158/1538-7445.AM2013-3677