The Resorcylic Acid Lactone Hypothemycin Selectively Inhibits the Mitogen-Activated Protein Kinase Kinase-Extracellular Signal-Regulated Kinase Pathway in Cells

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  • Fukazawa Hidesuke
    Department of Bioactive Molecules, National Institute of Infectious Diseases
  • Ikeda Yoshimi
    Department of Bioactive Molecules, National Institute of Infectious Diseases Division of Basic Biological Sciences, Faculty of Pharmacy, Keio University
  • Fukuyama Mari
    Department of Bioactive Molecules, National Institute of Infectious Diseases
  • Suzuki Takeshi
    Division of Basic Biological Sciences, Faculty of Pharmacy, Keio University
  • Hori Hiroshi
    Department of Life Science, Tamagawa University
  • Okuda Toru
    Mycology and Metabolic Diversity Research Center, Tamagawa University Research Institute
  • Uehara Yoshimasa
    Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmacy

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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.

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