Activation of cytosolic phospholipase A2α by epidermal growth factor (EGF) and phorbol ester in HeLa cells: different effects of inhibitors for EGF receptor, protein kinase C, Src, and C-Raf

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  • Matsuzawa Yasuo
    Department of Internal Medicine, Toho University School of Medicine, Sakura Hospital, Japan
  • Kiuchi Yoshiaki
    Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
  • Toyomura Kaori
    Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
  • Matsumoto Ikiru
    Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
  • Nakamura Hiroyuki
    Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
  • Fujino Hiromichi
    Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
  • Murayama Toshihiko
    Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Japan
  • Kawashima Tatsuo
    Department of Internal Medicine, Toho University School of Medicine, Sakura Hospital, Japan

書誌事項

タイトル別名
  • Activation of Cytosolic Phospholipase A2.ALPHA. by Epidermal Growth Factor (EGF) and Phorbol Ester in HeLa Cells: Different Effects of Inhibitors for EGF Receptor, Protein Kinase C, Src, and C-Raf
  • Activation of cytosolic phospholipase A2 a by epidermal growth factor EGF and phorbol ester in HeLa cells different effects of inhibitors for EGF receptor protein kinase C Src and C Raf

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説明

In several types of cancer cells, prostaglandins produced via the over-expression of epidermal growth factor receptor (EGFR) and cyclooxygenases regulate cell growth. We investigated the signaling mechanisms for the release of arachidonic acid (AA, a precursor for prostaglandins) in human cervical carcinoma HeLa cells. Treatment with EGF and 4β-phorbol 12-myristate 13-acetate (PMA) with A23187 released AA accompanied by the phosphorylation of extracellular signal-regulated kinases (ERK1/2). Pharmacological experiments showed that the responses (ERK phosphorylation and AA release) induced by EGF and PMA were mediated by a mitogen-activated protein kinase/ERK kinase (MEK) – ERK – α-type cytosolic phospholipase A2 (cPLA2α) pathway and that EGFR couples with the pathway in a manner insensitive to sorafenib, an inhibitor of B- and C-Raf, enzymes upstream of MEK. Activation of protein kinase C by PMA couples with the pathway partly in a sorafenib-sensitive and probably C-Raf–mediated manner and partly in a family of Src tyrosine kinases (Src)–dependent and sorafenib-insensitive manner. Co-treatment with sorafenib and an inhibitor of Src family members additionally inhibited the PMA-induced release of AA. Cross-talk between EGFR and protein kinase C was not observed. In human lung carcinoma A549 cells, the release of AA by EGF was insensitive to sorafenib. Possible mechanisms for the sorafenib-insensitive activation of the MEK–ERK–cPLA2α pathway are discussed.<br>

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