Abstract 4421: PDE5 inhibitors suppress proliferation and augment the epithelial barrier by activating PKG2 in the colon

Abstract

Abstract Increasing cGMP levels has emerged as a potentially important suppressor of tumorigenesis in the colon, but the downstream signaling is poorly defined and a viable therapeutic strategy remains to be established. The present study has tested whether type 2 cGMP-dependent protein kinase (PKG2) mediates the homeostatic effects of cGMP in the colon. In addition, the feasibility of using phosphodiesterase 5 (PDE5) inhibitors therapeutically to increase cGMP levels in the colon mucosa has been examined. PKG2 is a central effector of cGMP in enterocytes, and consistent with a growth-inhibitory and differentiation-promoting role, knockout animals showed crypt hyperplasia and reduced mature goblet cells in the colonic mucosa. This phenotype is similar to guanylyl-cyclase C (GCC) knockout animals, which have also been reported to exhibit increased susceptibility to colon tumorigenesis. The possibility that PKG2 signaling might be activated pharmacologically, was examined using PDE5 inhibitors to regulate colonic proliferation and differentiation. These experiments demonstrated that intraperitoneal administration of clinically relevant PDE5 inhibitors provoked a rapid increase cGMP levels in the colon mucosa of mice. Moreover, prolonged treatment with PDE5 inhibitors led to reduced proliferation in the colonic crypts and a dramatic increase in mature goblet cells. Consistent with the importance of PKG2 in this process, the PDE5 inhibitors did not inhibit proliferation or increase goblet cell numbers in PKG2 knockout animals. The increase in goblet cell density in PDE5 inhibitor-treated animals was striking (50%, 85%, and 44% relative to controls in the ascending, transverse and descending colon respectively). Reduced basal epithelial apoptosis measured in PDE5 inhibitor treated animals suggested the the increased goblet cells could have a barrier-protective effect. To test this possibility further, the effect of PDE5 inhibitor treatment on epithelial damage by dextran sulfate sodium was measured. These studies demonstrated a significant attenuation of disease activity by PDE5 inhibitor treatment in this colitis model. In summary, our results demonstrate a central role for PKG2 in the regulation of proliferation and differentiation in the colon mucosa. In addition, this pathway can be exploited using PDE5 inhibitors, suggesting that these agents could be part of a novel therapeutic strategy for colon cancer prevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4421. doi:1538-7445.AM2012-4421