The resorcylic acid lactone hypothemycin selectively inhibits the mitogen-activated protein kinase kinase-extracellular signal-regulated kinase pathway in cells.

Abstract

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.

• Authors: Hidesuke Fukazawa, Yoshimi Ikeda, Mari Fukuyama, Takeshi Suzuki, Hiroshi Hori, Toru Okuda, Yoshimasa Uehara
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 33 Issue 2 Pg. 168-73 ( 2010) ISSN: 1347-5215 [Electronic] Japan
• PMID: 20118535 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Butadienes
• Flavonoids
• Growth Inhibitors
• Nitriles
• Protein Kinase Inhibitors
• U 0126
• hypothemycin
• Zearalenone
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase Kinases
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Animals
• Butadienes (pharmacology)
• Cell Line, Tumor
• Cell Transformation, Neoplastic (drug effects)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, physiology)
• Fibroblasts (drug effects, enzymology)
• Flavonoids (pharmacology)
• Growth Inhibitors (pharmacology)
• Humans
• Kidney (cytology, drug effects, enzymology)
• MAP Kinase Signaling System (drug effects, physiology)
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, physiology)
• Nitriles (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Rats
• Zearalenone (analogs & derivatives, pharmacology)