Hepatocyte growth factor induces anoikis resistance by up-regulation of cyclooxygenase-2 expression in uterine endometrial cancer cells

Abstract

Cyclooxygenase-2 (COX-2) has been implicated in the promotion of carcinogenesis. Although the role of COX-2 in endometrial cancer remains unclear, recent experiments suggest that COX-2 antagonizes cell apoptosis, increases the invasiveness of malignant cells, and promotes angiogenesis. Hepatocyte growth factor (HGF) is a mesenchymal-derived cytokine and the interaction between HGF and its tyrosine kinase receptor, c-Met proto-oncogene, is associated with tumor progression and metastasis. To investigate the molecular mechanism of HGF-induced anoikis resistance, we analyzed the signal transduction and COX-2 expression in endometrial cancer cells. Here, we show i) the expression of COX-2 protein significantly increased in a dose-dependent manner after HGF stimulation in endometrial cancer cell lines (HEC-IB and RL95-2), reaching 200-270% stimulation at the highest doses of HGF tested (40 ng/ml); ii) flow cytometry and TUNEL analyses revealed that HGF significantly inhibited anoikis of RL95-2 cells; iii) phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), but not mitogen-activated protein kinase/ERK kinase (MEK) inhibitor (PD98059), specifically blocked HGF-mediated anoikis resistance in RL95-2 cells; and iv) COX-2 inhibitor, Meloxicam, abrogated HGF-mediated anoikis resistance. Our data suggest that HGF induces anoikis resistance in endometrial cancer cells possibly through PI3K/Akt pathway-dependent up-regulation of COX-2 expression.