TI - Cyclic GMP -dependent protein kinase activation and induction by exisulind and CP461 in colon tumor cells . 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 Ibeta protein expression . beta-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 beta-catenin . These data indicate that exisulind and analogs activate and induce PKG , resulting in increased phosphorylation of beta-catenin and enhanced apoptosis to promote colon tumor cell death .