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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概要

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• 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.

著者

• NAKAMURA Hiroyuki

  Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University

• FUJINO Hiromichi

  Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University

• MURAYAMA Toshihiko

  Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University

• Muramatsu Yuki

  Laboratory Of Organic Chemistry Graduate School Of Pharmaceutical Sciences Chiba University

• KAWASHIMA Tatsuo

  Department of Internal Medicine, Toho University Sakura Medical Center

• MATSUZAWA Yasuo

  Department of Internal Medicine, Toho University Sakura Medical Center

• Fujino Hiromichi

  Laboratory Of Chemical Pharmacology Graduate School Of Pharmaceutical Sciences Chiba University

• Murayama Toshihiko

  Laboratory Of Chemical Pharamacology Graduate School Of Pharmaceutical Sciences Chiba University

• Kiuchi Yoshiaki

  Laboratory Of Chemical Pharmacology Graduate School Of Pharmaceutical Sciences Chiba University

• Matsuzawa Yasuo

  Department Of Internal Medicine Toho University School Of Medicine Sakura Hospital

• Matsuzawa Yasuo

  Department Of Internal Medicine Toho University Sakura Medical Center

• TOYOMURA Kaori

  Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University

• MATSUMOTO Ikiru

  Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University

• Toyomura Kaori

  Laboratory Of Chemical Pharmacology Graduate School Of Pharmaceutical Sciences Chiba University

• Kawashima Tatsuo

  Department Of Internal Medicine Toho University School Of Medicine Sakura Hospital

• Matsumoto Ikiru

  Laboratory Of Chemical Pharmacology Graduate School Of Pharmaceutical Sciences Chiba University

• Nakamura Hiroyuki

  Laboratory Of Chemical Pharmacology Graduate School Of Pharmaceutical Sciences Chiba University

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