RADICICOL LEADS TO SELECTIVE DEPLETION OF RAF KINASE AND DISRUPTS K-RAS-ACTIVATED ABERRANT SIGNALING PATHWAY

Activation of Ras leads to the constitutive activation of a downstream phosphorylation cascade comprised of Raf-1, mitogen-activated protein kinase (MAPK) kinase, and MAPK, We have developed a yeast-based assay in which the Saccharomyces cerevisiae mating pheromone-induced MAPK p athway relied on co-expression of K-Ras and Raf-1, Radicicol, an antif ungal antibiotic, was found to inhibit the K-ras signaling pathway rec onstituted in yeast, In K-ras-transformed, rat epithelial, and K-ras-a ctivated, human pancreatic carcinoma cell lines, radicicol inhibited K Ras-induced hyperphosphorylation of Erk2, In addition, the level of R af kinase was significantly decreased in radicicol-treated cells, wher eas the levels of K-Ras and MAPK remained unchanged, These results sug gest that radicicol disrupts the K-Ras-activated signaling pathway by selectively depleting Raf kinase and raises the possibility that pharm acological destabilization of Raf kinase could be a new and powerful a pproach for the treatment of K-ras-activated human cancers.