ADENOMATOUS POLYPOSIS-COLI, PROTEIN-KINASES, PROTEIN-TYROSINE-PHOSPHATASE - THE EFFECT OF SULINDAC

A putative explanation of the effect of sulindac on adenomatous colon and duodenal polyps from clinical observations and related in vitro ex periments is presented. In cells with mutant APC genes, persistent hig h prostaglandin content of polyps leads to desensitization, downregula tion of adenylate cyclase, uncoupling of cAMP synthesis from prostagla ndin, and inactivation of protein kinase A (PKA). It is suggested that in normal cells, (APC) protein binds to catenins and microtubules to maintain structure and contribute to cell-cell communication, adherenc e, and the dephosphorylated state, a necessary condition for such func tions. Cells with mutant APC product become isolated, deprived of comm unication and adhesion to other epithelial cells, overphosphorylated, and without corrective capability. The latter is largely due to downre gulation of cAMP synthesis and protein kinase A activity secondary to high prostaglandin. Three main biochemical defects ensue: (1) the rest rictive influence of PKA catalyzed phosphorylation of Raf-1 kinase and resultant effects on the MAP kinase cascade and transcription is lost , (2) the transcription of immediate early genes, including cyclooxyge nase is stimulated, and (3) the stimulation of protein tyrosine phosph atase (PTPase) by PKA is in abeyance. These putative abnormalities are reversed by inhibition of cyclooxygenase-1 by sulindac, cAMP synthesi s and PKA activity return to normal. PKA catalyzed phosphorylations bl ock Raf-1 kinase at the confluence of the Pas and protein kinase C pat hways. The MAP kinase cascade is inhibited as is transcription of imme diate early genes. At the same time PKA stimulates PTPase, which depho sphorylates the cytoskeleton and restores cell-cell communication, adh erence, and structure. The transformed phenotype is circumvented by ad justment of the phosphorylation state and mutant cells rejoin the epit helial community. The redox state of cytoplasm in mutant cells may be shifted toward reduction. (C) 1995 Wiley-Liss, Inc.