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.
Highlights
Overexpression of cyclooxygenase-2 (COX-2) has been detected in malignant tumors of a variety of tissues, including colon, prostate, lung, breast, and uterine cervix [1,2,3,4,5]
We further investigated whether epidermal growth factor receptor (EGFR) down-regulation by COX-2 is specific to HCT-116-COX-2 cells or if it is a general phenomenon in other tumor cells
When exogenous prostaglandin E2 (PGE2) was administered to H460-Mock cells, the phospho-PKCα/β levels were reduced (Fig. 5C). These results indicate that COX-2–produced PGE2 is not associated with PKCα/β activation and does not mediate EGFR down-regulation in the tested cancer cell lines
Summary
Overexpression of cyclooxygenase-2 (COX-2) has been detected in malignant tumors of a variety of tissues, including colon, prostate, lung, breast, and uterine cervix [1,2,3,4,5]. COX-2 is known to play an important role in carcinogenesis by stimulating growth, survival, invasion, metastasis, and angiogenesis of tumor cells [3, 4, 6,7,8,9], but its exact role in cancer development has not been well understood. COX-2 is a 72-kDa protein with 604 amino acids, localized primarily to the endoplasmic reticulum and nuclear membrane. COX-2 has an epidermal growth factor (EGF)–like domain at its NH2 terminus that functions in Ca2+-related signaling pathways such as the protein kinase C (PKC) pathway, whereas the COOH terminus has a peroxidase domain that acts in cellular oxidation and reduction. Cyclooxygenase activity of COX-2 transforms arachidonic acid into intermediate prostaglandin G2, which is subsequently converted to prostaglandin H2 through peroxidase activity, and prostaglandins [prostaglandin E2 (PGE2), prostaglandin D2, prostaglandin F2α, thromboxane A, etc.] are produced by various synthases [6, 11, 12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
