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

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• 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.

• 公益社団法人　日本薬学会の論文

著者

• SUZUKI Takeshi

  Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute

• UEHARA Yoshimasa

  Department of Bioactive Molecules, National Institute of Infectious Diseases

• Hori Hiroshi

  Department of Biology, Nagoya University

• OKUDA Toru

  Mycology and Metabolic Diversity Research Institute, Tamagawa University Research Institute

• Hori Hiroshi

  Department Of Applied Biological Chemistry Tamagawa University

• IKEDA Yoshimi

  Department of Pharmacological Research Laboratories, Pharmaceutical Research Center, Kyowa Hakko Kog

• FUKAZAWA Hidesuke

  Department of Bioactive Molecules, National Institute of Infectious Diseases

• Uehara Yoshimasa

  Department Of Bioactive Molecules National Institute Of Infectious Diseases

• Okuda Toru

  Mycology And Metabolic Diversity Research Institute Tamagawa University Research Institute

• Ikeda Yoshimi

  Department Of Pharmacological Research Laboratories Pharmaceutical Research Center Kyowa Hakko Kogyo

• 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

• Ikeda Yoshimi

  Department of Bioactive Molecules, National Institute of Infectious Diseases

• Okuda Toru

  Mycology and Metabolic Diversity Research Center, Tamagawa University Research Institute

• Okuda Toru

  Mycology & Metabolic Diversity Research Center, Tamagawa University Research Institute

• HORI Hiroshi

  Department of Agricultural Chemistry, Faculty of Agriculture, Tamagawa University

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