RRC ID 10777
著者 Matsuzawa Y, Kiuchi Y, Toyomura K, Matsumoto I, Nakamura H, Fujino H, Murayama T, Kawashima T.
タイトル Activation of cytosolic phospholipase A2alpha 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.
ジャーナル J Pharmacol Sci
Abstract 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 4beta-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-alpha-type cytosolic phospholipase A(2) (cPLA(2)alpha) 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-cPLA(2)alpha pathway are discussed.
巻・号 111(2)
ページ 182-92
公開日 2009-10-1
DOI 10.1254/jphs.09201fp
PII JST.JSTAGE/jphs/09201FP
PMID 19783865
MeSH Benzenesulfonates / pharmacology Cytosol / metabolism Enzyme Activation / drug effects Enzyme Inhibitors / pharmacology* Epidermal Growth Factor / pharmacology* ErbB Receptors / antagonists & inhibitors Group IV Phospholipases A2 / metabolism* HeLa Cells Humans Mitogen-Activated Protein Kinase 1 / metabolism Mitogen-Activated Protein Kinase 3 / metabolism Models, Biological Niacinamide / analogs & derivatives Phenylurea Compounds Phosphorylation / drug effects Protein Kinase C / antagonists & inhibitors Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins c-raf / antagonists & inhibitors Pyridines / pharmacology Signal Transduction / drug effects Sorafenib Temperature Tetradecanoylphorbol Acetate / pharmacology* Time Factors src-Family Kinases / antagonists & inhibitors
IF 2.835
引用数 11
WOS 分野 PHARMACOLOGY & PHARMACY
リソース情報
ヒト・動物細胞 A549(RCB0098)