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

Abstract

Overexpression of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) has been detected in many types of cancer. Although COX-2 and EGFR are closely related to each other, the exact mechanism of COX-2 in tumors has not been well understood. In this study, we investigated the relationship between COX-2 and EGFR in cancer cells. Using two cell lines stably overexpressing COX-2 (HCT-116-COX-2 and H460-COX-2) and a stable line of COX-2 knockdown MOR-P cells, we analyzed patterns of COX-2 and EGFR expression. To observe the effects of COX-2 on EGFR expression and activity, we did comparative analyses after treatment with various drugs (EGF, celecoxib, prostaglandin E 2 , gefitinib, Ro-31-8425, PD98059, and SP600125) in HCT-116-Mock versus HCT-116-COX-2 cells and H460-Mock versus H460-COX-2 cells. Overexpression of COX-2 specifically down-regulated EGFR expression at the level of transcription. COX-2-overexpressing cells have a decreased sensitivity to gefitinib. COX-2 induced activation of extracellular signal-regulated kinase (ERK) and c-Jun NH 2 -terminal kinase (JNK) but suppressed Akt activation. JNK inhibition by SP600125, a specific JNK inhibitor, resulted in restoration of EGFR levels in COX-2-overexpressing cells, whereas ERK inhibition by PD98059 did not. Overexpressed COX-2 negatively regulates EGFR expression via JNK activation, leading to gefitinib resistance. COX-2 may also regulate ERK activity independently of EGFR. Therefore, resistance of COX-2-overexpressing cells to gefitinib may be due to decreased expression of EGFR by JNK activation and EGFR-independent elevation of ERK activity by COX-2. The ability of COX-2 to inhibit EGFR expression and gefitinib effects may have significance in clinical cancer therapy.

Transgenic Mice Expressing Cyclooxygenase-2 in Hepatocytes Reveal a Minor Contribution of This Enzyme to Chemical Hepatocarcinogenesis

“…39 The effect of COX-2-dependent PGs on these signaling pathways have been recently studied using cell lines stably overexpressing COX-2. 40 Our data in COX-2 Tg hepatocyte-like cells verify moderate activation of JNK, Erk, and p38 in CHL-C cells.…”

Lapatinib-Mediated Cyclooxygenase-2 Expression via Epidermal Growth Factor Receptor/HuR Interaction Enhances the Aggressiveness of Triple-Negative Breast Cancer Cells

“…4F). In addition to its potential role in tumor promotion and progression, overexpression of COX-2 has been suggested to promote resistance to EGFR TKIs in both EGFR-dependent and EGFR-independent manners (Krysan et al, 2005;Kim et al, 2009), and addition of specific COX-2 inhibitors can synergize the effect of EGFR TKIs in some preclinical studies Zhang et al, 2005;Buchanan et al, 2007). The induction of COX-2 transcription by EGFR is well documented and mostly relies on EGFR tyrosine kinase activity (Rogers et al, 2005).…”

ANGPTL4 Induction by Prostaglandin E2 under Hypoxic Conditions Promotes Colorectal Cancer Progression

“…It has been reported that COX-2 overexpressing cancer cells are more resistant to doxorubicin and gefitinib (46, 47). Moreover, STAT1 has been shown to play a role in chemo- and radio-resistance.…”