The resorcylic acid lactone hypothemycin selectively inhibits the mitogen-activated protein kinase kinase-extracellular signal-regulated kinase pathway in cells.
The resorcylic acid lactone hypothemycin has been shown to inactivate protein kinases by binding to a cysteine conserved in 46 protein kinases, including mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase (ERK) and platelet-derived growth factor receptor (PDGFR). We assessed the selectivity of hypothemycin in cellular contexts. Hypothemycin normalized the morphology and inhibited anchorage-independent growth of Ki-ras transformed normal rat kidney (NRK) cells with selectivity and potency comparable to or greater than that of the MEK inhibitor U0126. In Ki-ras-transformed and phorbol 12-myristate 13-acetate (PMA)-treated NRK cells, hypothemycin blocked ERK activation but showed a minimal effect on autophosphorylation of protein kinase D1 (PKD1), another kinase containing the conserved cysteine. Hypothemycin potently inhibited PDGFR autophosphorylation and activation of the MEK-ERK pathway in platelet-derived growth factor (PDGF)-treated NRK cells. However, the phosphoinositide-3-kinase (PI3K) pathway was only modestly attenuated. Hypothemycin also inhibited growth factor- and anchorage-independent growth of human cancer cell lines with a constitutively active MEK-ERK pathway. Although hypothemycin has the potential to inactivate various protein kinases, the results indicate that in intracellular environments, hypothemycin can inhibit the MEK-ERK axis with sufficient selectivity to normalize transformed phenotypes of cells dependent on this pathway.
Fukazawa
Hidesuke
H
Department of Bioactive Molecules, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
Ikeda
Yoshimi
Y
Fukuyama
Mari
M
Suzuki
Takeshi
T
Hori
Hiroshi
H
Okuda
Toru
T
Uehara
Yoshimasa
Y
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005419:Flavonoids / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D015025:Zearalenone / Q000031:analogs & derivatives / Q000494:pharmacology
D002070:Butadienes; D005419:Flavonoids; D006131:Growth Inhibitors; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C113580:U 0126; C120440:hypothemycin; D015025:Zearalenone; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one