Abstract
Abstract Previously, we showed that short term (3 weeks) treatment of ApcMin/+ mice with the COX-2 inhibitor, celecoxib, reduced intestinal tumorigenesis, but long term drug treatment (5 months) increased intestinal tumors, stromal myofibroblasts, fibrosis, and expression of COX-2, PGE2, and TGFβ1, 2, 3 (TGFβ). Because COX-2 inhibitors are often used in patients with chronic inflammation, we examined the effects of celecoxib in Apc+/+ mice by immunoblotting and immunohistochemistry. Short term treatment induced canonical TGFβ signaling with increased expression of TGFβ and its receptor, effector, and targeted product (TβRII, Smad4, and PAI-1). In parallel, integrin signaling was suppressed with reduced expression of β1 integrin, active Focal Adhesion Kinase (FAK-p-Y397), Integrin-Linked Kinase, and the RhoA inhibitor, p190RhoGAP. Enterocyte differentiation but not proliferation was reduced relative to controls. Although COX-2 and TGFβ expression remained higher than basal levels, long term treatment reversed the effects on canonical TGFβ and integrin signaling, resulting in increased proliferation and differentiation. These results suggest that in the normal intestine PGE2 plays a role in modulating mechanical changes in cell-matrix adhesion via crosstalk between TGFβ and integrins. The mechanism for this could depend on the ability of PGE2 to increase [cAMPi] and Protein Kinase A activity. Chronic exposure to celecoxib may promote tumorigenesis by enhancing enterocyte positive growth regulation via integrins, while suppressing its negative regulation via TGFβ. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2863.
Published Version
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