Nonsteroidal anti-inflammatory drugs (
NSAID) such as
sulindac sulfide (SS) display promising
antineoplastic properties, but toxicities resulting from COX inhibition limit their clinical use. Although COX inhibition is responsible for the anti-inflammatory activity of SS, recent studies suggest that
phosphodiesterase (PDE) 5 inhibition and activation of cyclic
guanosine monophosphate (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
protein kinase G (PKG) by SS was associated with increased β-
catenin phosphorylation, decreased β-
catenin mRNA and
protein levels, reduced β-
catenin nuclear localization, decreased
T-cell factor/
lymphoid enhancer factor (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.