RT Journal Article SR Electronic T1 Cyclic GMP-Dependent Protein Kinase Activation and Induction by Exisulind and CP461 in Colon Tumor Cells JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 583 OP 592 VO 299 IS 2 A1 Li Liu A1 Han Li A1 Tashandra Underwood A1 Marti Lloyd A1 Mary David A1 Gerhard Sperl A1 Rifat Pamukcu A1 W. Joseph Thompson YR 2001 UL http://jpet.aspetjournals.org/content/299/2/583.abstract AB These studies report on the activation and induction of cGMP-dependent protein kinase (PKG) by exisulind and analogs and test the hypothesis that PKG is involved in the induction of apoptosis in colon tumor cells. Exisulind and analogs are proapoptotic drugs developed as inhibitors of cGMP phosphodiesterase gene families 5 and 2 that have been shown to sustain increased cGMP in SW480 and HT29 cells. At concentrations that induced apoptosis, both exisulind and CP461 increased PKG activity in SW480 cell supernatants. PKG activation was dose-dependent and sustained. Activation of PKG by exisulind and analogs was also seen in the colon tumor cell lines HT29, T84, and HCT116. The guanylyl cyclase activators YC-1 and guanylin increased PKG activity secondary to increased cellular cGMP and induced apoptosis in colon tumor cells. Exisulind and CP461 had no direct effect on purified PKG activity or on basal and stimulated PKG activity from cell supernatants. An additional effect of exisulind after 8 h of drug treatment was a dose-dependent increase of PKG Iβ protein expression. β-Catenin, a potential new substrate for PKG, whose regulation influences apoptosis, was phosphorylated by PKG in vitro.32P-labeled cells treated with exisulind showed increased phosphorylation of β-catenin. These data indicate that exisulind and analogs activate and induce PKG, resulting in increased phosphorylation of β-catenin and enhanced apoptosis to promote colon tumor cell death. The American Society for Pharmacology and Experimental Therapeutics