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 pathway relied on co-expression of K-Ras and Raf-1. Radicicol, an antifungal antibiotic, was found to inhibit the K-ras signaling pathway reconstituted in yeast. In K-ras-transformed, rat epithelial, and K-ras-activated, human pancreatic carcinoma cell lines, radicicol inhibited K-Ras-induced hyperphosphorylation of Erk2. In addition, the level of Raf kinase was significantly decreased in radicicol-treated cells, whereas the levels of K-Ras and MAPK remained unchanged. These results suggest that radicicol disrupts the K-Ras-activated signaling pathway by selectively depleting Raf kinase and raises the possibility that pharmacological destabilization of Raf kinase could be a new and powerful approach for the treatment of K-ras-activated human cancers.
Soga
S
S
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co. Ltd., Asahi-machi 3-6-6, Machida-shi, Tokyo 194, Japan.
Kozawa
T
T
Narumi
H
H
Akinaga
S
S
Irie
K
K
Matsumoto
K
K
Sharma
S V
SV
Nakano
H
H
Mizukami
T
T
Hara
M
M
D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011905:Genes, ras; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D010190:Pancreatic Neoplasms / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors*; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D007783:Lactones; D018942:Macrolides; D011994:Recombinant Proteins; D019908:Proto-Oncogene Proteins c-raf; C035359:monorden