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) |