Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac sulfide (SS) display promising antineoplastic properties, but toxicities resulting from cyclooxygenase (COX) inhibition limit their clinical use. While COX inhibition is responsible for the anti-inflammatory activity of SS, recent studies suggest that phosphodiesterase (PDE) 5 inhibition and activation of cGMP signaling are closely associated with its ability to induce apoptosis of tumor cells. However, the underlying mechanisms responsible for apoptosis induction, factors that influence sensitivity of tumor cells to SS, and the importance of PDE5 for breast tumor cell growth have not been established. Here we show that SS can induce apoptosis of breast tumor cells, which predominantly rely on PDE5 for cGMP hydrolysis, but not normal mammary epithelial cells, which rely on PDE isozymes other than PDE5 for cGMP hydrolysis. Inhibition of PDE5 and activation of PKG by SS was associated with increased beta-catenin phosphorylation, decreased beta-catenin mRNA and protein levels, reduced beta-catenin nuclear localization, decreased Tcf/Lef promoter activity, and decreased expression of Wnt/beta-catenin regulated proteins. Suppression of PDE5 with siRNA or known PDE5 inhibitors was sufficient to selectively induce apoptosis and attenuate beta-catenin mediated transcription in breast tumor cells with minimal effects on normal mammary epithelial cells. These findings provide evidence that SS induces apoptosis of breast tumor cells through a mechanism involving inhibition of PDE5 and attenuation of oncogenic Wnt/beta-catenin mediated transcription. We conclude that PDE5 represents a novel molecular target for the discovery of safer and more efficacious drugs for breast cancer chemoprevention.
- Received February 21, 2011.
- Revision received March 22, 2011.
- Accepted March 29, 2011.
- Copyright © 2011, American Association for Cancer Research.