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.

Downregulation of COX-2 and CYP 4A signaling by isoliquiritigenin inhibits human breast cancer metastasis through preventing anoikis resistance, migration and invasion

“…COX-2 and PGE 2 play important roles in breast cancer metastasis (Ma et al, 2006;Ho et al, 2013;Sun et al, 2013) and contribute to anoikis resistance in several cancer cell lines (Zeng et al, 2002;Choi et al, 2005;Kanayama et al, 2008;Yoshizawa et al, 2011). PGE 2 suppresses detachmentinduced apoptosis in rat intestinal epithelial cells, and prostaglandin receptor (EP) 4, one of the PGE 2 receptors, is related to delayed anoikis by PGE 2 (Joseph et al, 2005).…”

Anoikis: an emerging hallmark in health and diseases

“…Indeed, in uterine endometrial cancer cells, HGF induces anoikis resistance through a PI3K-Akt pathwaydependent up-regulation of cyclooxygenase-2 (COX-2) expression. Similarly, Met receptor induces anoikis resistance in head and neck squamous cell carcinoma cells by activation of ERK and PI3K/Akt signalling [104]. Moreover, recently it has been reported that breast cancer cells undergoing EMT acquire many of the properties of cancer stem cells [105,106].…”

NK4, an HGF antagonist, prevents hematogenous pulmonary metastasis by inhibiting adhesion of CT26 cells to endothelial cells

“…Tumor cells lacking anchorage could escape from anoikis by forming multicellular aggregates through FAK phosphorylation [39]. Also, Kanayama et al [40] reported that HGF induces anoikis resistance by up-regulation of cyclooxygenase-2 expression in uterine endometrial cancer cells. In contrast to their studies, we did not observe FAK phosphorylation in CT26 transfectants in suspension even after addition of HGF.…”