Inhibition of PDE5 by Sulindac Sulfide Selectively Induces Apoptosis and Attenuates Oncogenic Wnt/β-Catenin–Mediated Transcription in Human Breast Tumor Cells

Abstract

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 β-catenin phosphorylation, decreased β-catenin mRNA and protein levels, reduced β-catenin nuclear localization, decreased Tcf/Lef promoter activity, and decreased expression of Wnt/β-catenin regulated proteins. Suppression of PDE5 with siRNA or known PDE5 inhibitors was sufficient to selectively induce apoptosis and attenuate β-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/β-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.

The Role of NSAIDs in Breast Cancer Prevention and Relapse: Current Evidence and Future Perspectives

“…Because inflammation is closely associated with tumorigenesis, COX-2 has been shown to be overexpressed in precancerous and malignant lesions [33,34,35]. Its inhibition and the suppression of prostaglandin synthesis is widely accepted as the primary mechanism of the anticancer activity of NSAIDs.…”

“…However, some studies have concluded that a rather COX-independent mechanism may either contribute to or be exclusively responsible for the chemopreventive activity of NSAIDs [34,35,36]. …”

cGMP-dependent Protein Kinase Iβ Regulates Breast Cancer Cell Migration and Invasion via a Novel Interaction with the Actin/Myosin-associated Protein Caldesmon

“…It was shown that PKG has both pro-and anti-proliferative effects on various tumor cell types. In some colon and breast cancer cells, PKG activation inhibits proliferation and increases apoptosis (Deguchi et al, 2004;Tinsley et al, 2011;Whitt et al, 2012), and these effects may be mediated by decreasing b-catenin levels (Tinsley et al, 2011;Whitt et al, 2012). In stark contrast, PKG facilitates pro-proliferative/anti-apoptotic signaling in neuronal, ovarian and lung tumor cells lines through inhibition of caspase activity and increasing expression of anti-apoptotic genes (Kim et al, 1999;Leung et al, 2010;Wong et al, 2012).…”

Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α

“…As mentioned above, another component reported to play an important role in the preconditioning pathways is PKG (22). Sulindac has been reported to be an inhibitor of PDE5, which raises cGMP levels and activates PKG (9). In the present study we tested the effect of inhibiting PKG using the known PKG inhibitor, Rp-Br-8-PET-cGMPS.…”

“…Sulindac has also been shown to be an inhibitor of phosphodiesterase type 5 (PDE5) (9) and has been reported to react with both the peroxisome proliferator activator receptors (PPARs) and a truncated retinoic acid receptor (RXR) (10). The members of the PPAR nuclear receptor family are involved in certain key protective pathways in a variety of cell types and are known to complex with the RXR family (11).…”