Abstract 3687: Curcumin both inactivates and induces selenoprotein thioredoxin reductase: dual regulation influences curcumin-induced apoptosis in prostate cancer cells
Authors: Gopalakrishna Rayudu , Schiffman Jason Eric , Mowatt Kelley , Gundimeda Usha 
Published: June 2012

Abstract
Curcumin induces growth inhibition and cell death in various prostate cancer cell types. The exact mechanism is not known. Previous studies have shown that selenoprotein thioredoxin reductase (TR) is a molecular target for curcumin, which inactivates this enzyme by covalently reacting with its selenocysteine residue. This modification converts this reductase into an oxidase, causing the production of superoxide radicals. Since TR either protects cells from oxidative stress-induced cell death or induces oxidative stress after its modification by curcumin, we determined whether the expression of this enzyme is altered by curcumin treatment. TR from cell extracts of both androgen-dependent LNCaP and androgen-independent DU145 cells was eluted in two peaks (designated as peak 1 and peak 2) during DEAE-cellulose chromatography. Upon treatment with curcumin for 5 h, peak 1 TR activity was substantially decreased in both cell types. Nevertheless, peak 2 TR activity was unaffected by curcumin treatment during this period. Curcumin as low as 10 μM inactivated peak 1 activity in intact cells. Conversely, upon prolonged treatment (24 h), curcumin (5 to 25 μM) induced a 2- to 3-fold increase in TR activity in both peak 1 and peak 2. Curcumin concentrations as low as 10 μM were enough to induce an increase in TR activity in DU145 cells. Western immunoblot analysis revealed a two-fold increase in both cytosolic isoenzyme TR1 and mitochondrial TR2 upon treatment with curcumin for 24 h. Antioxidant N-acetylcysteine minimized curcumin-induced cell death, suggesting the involvement of reactive oxygen species in this process. N-Acetylcysteine also blocked the curcumin-induced increase in TR, suggesting the involvement of reactive oxygen species in the induction of TR as well. As an adaptive response to oxidative stress, cells may be inducing TR to minimize cell death. However, this study cannot exclude the possibility that the induced TR, after covalent modification by curcumin, plays an opposite role to induce cell death. Nonetheless, this possibility is unlikely given that neither TR activity nor immunoreactive protein were elevated with 50 μM curcumin which frankly induced apoptosis in these cell types. It is thus most likely that induced TR exposed to low concentrations (5 to 20 μM) of curcumin inhibits cell death. This is particularly important that the plasma concentration of curcumin is lower than that required to induce cell death in vitro. Therefore, it is possible that agents that prevent induction of TR may sensitize prostate cancer cells to curcumin. This study was supported by the National Cancer Institute grant CA099216.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3687. doi:10.1158/1538-7445.AM2011-3687