Prostaglandin E2 enhances mitogen-activated protein kinase/Erk pathway in human cholangiocarcinoma cells: involvement of EP1 receptor, calcium and EGF receptors signaling.
COX-2-derived PGE2 has been implicated in the development of various types of cancers. However, the exact mechanism of PGE2-induced cancer cell proliferation and survival is still unclear. In the current study, the mechanism underlying PGE2-enhanced Erk phosphorylation in human cholangiocarcinoma cells was determined. The intracellular concentration of calcium in three cholangiocarcinoma cell lines was measured using a laser confocal scanning microscope and the expression levels of Erk and EGFR phosphorylation were determined by Western blot analyses. The activation of EP1 receptors involved in PGE2-stimulated Erk activation and increasing the intracellular concentration of calcium was elucidated using selective EP1 receptor subtype antagonists and agonist. The intracellular calcium chelator, BAPTA-AM, was shown to block PGE2-induced Erk and EGFR phosphorylation. PGE2-induced Erk phosphorylation was abrogated by pretreatment with the EGF receptor kinase inhibitor, AG1478. Our findings suggest that in human cholangiocarcinoma cells, PGE2-enhanced phosphorylation of Erk is, at least in part, mediated through EP1 receptors and EGFR phosphorylation induced by increases in the intracellular concentration of calcium.
Zhang
Li
L
Laboratory of Reproductive Medicine, Department of Pathology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, P.R. China.
Jiang
Li
L
Sun
Qiuyan
Q
Peng
Tao
T
Lou
Kexin
K
Liu
Ningbo
N
Leng
Jing
J
D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000502:physiology*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology*; D015232:Dinoprostone / Q000494:pharmacology*; D066246:ErbB Receptors / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D018078:Receptors, Prostaglandin E / Q000502:physiology*; D058306:Receptors, Prostaglandin E, EP1 Subtype
C545635:PTGER1 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone; D002118:Calcium