Prostaglandin E2 Activates Mitogen-Activated Protein Kinase/Erk Pathway Signaling and Cell Proliferation in Non–Small Cell Lung Cancer Cells in an Epidermal Growth Factor Receptor–Independent Manner

Abstract

Cyclooxygenase 2 (COX-2) overexpression is found in a wide variety of human cancers and is linked to all stages of tumorigenesis. Elevated tumor COX-2 expression is associated with increased angiogenesis, tumor invasion, suppression of host immunity and promotes tumor cell resistance to apoptosis. Previous reports have linked the COX-2 product prostaglandin E 2 (PGE 2 ) to the abnormal activation of the mitogen-activated protein kinase/Erk kinase pathway. Here we show that PGE 2 is able to rapidly stimulate Erk phosphorylation in a subset of non-small cell lung cancer (NSCLC) cell lines. This effect is not evident in bronchial epithelial cells. In contrast to previous reports in colon cancer, we found that Erk activation as well as cellular proliferation induced by PGE 2 was not inhibited by pretreatment of the cells with epidermal growth factor receptor (EGFR) inhibitors. Activation of the Erk pathway by PGE 2 was also resistant to src kinase inhibitors but sensitive to the protein kinase C inhibition. PGE 2 effects are mediated through four G protein-coupled receptors. Selective inhibition of EP receptors revealed the possible involvement of Ca 2+ -dependent signaling in PGE 2 -mediated activation of Erk. Our data indicate the presence of an EGFR-independent activation of the mitogen-activated protein kinase/Erk pathway by PGE 2 in NSCLC cells. These findings provide evidence for the possible link between tumor COX-2 overexpression and elevated Erk-mediated cancer cell proliferation and migration. Importantly, these findings suggest that COX-2 overexpression may contribute to EGFR inhibitor resistance in NSCLC. (Cancer Res 2005; 65(14): 6275-81)

Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells

“…Several studies report that PGE 2 induces PKC phosphorylation and results in EGFR inactivation (23,24). Therefore, we investigated whether COX-2 activates the PGE 2 -PKC pathway, which suppresses EGFR signaling.…”

“…According to several recent studies, PGE 2 can lead to PKC activation and activated PKC can inhibit EGFR signaling via phosphorylation of EGFR at Thr 654 (23,24). Therefore, we examined whether down-regulated EGFR expression seen in COX-2-overexpressing cells was due to activation of PKCα/β by elevated PGE 2 .…”

Proanthocyanidins Inhibit In vitro and In vivo Growth of Human Non–Small Cell Lung Cancer Cells by Inhibiting the Prostaglandin E2 and Prostaglandin E2 Receptors

“…PCR conditions were 5 min at 95°C followed by 35 cycles (25 for β-actin): 1 min at 95°C, 1 min at 58°C, and 1 min at 72°C, as reported (30).…”

Translation regulatory factor RBM3 is a proto-oncogene that prevents mitotic catastrophe

“…Known targets that lead to a tumorigenic phenotype include cyclooxygenase (COX)-2, interleukin (IL)-8 and vascular endothelial growth factor (VEGF) Dixon et al, 2001;Wang et al, 2005). COX-2 is the rate-limiting enzyme in the production of prostaglandins, an important mediator of various cellular processes including increased proliferation, apoptosis resistance and enhanced angiogenesis (Mukhopadhyay et al, 2003b;Krysan et al, 2005). COX-2 overexpression occurs in multiple tumors, and can be observed at various stages of tumorigenesis (Eberhart et al, 1994).…”