Cyclooxygenase-2 Up-Regulates Ataxia Telangiectasia and Rad3 Related through Extracellular Signal-Regulated Kinase Activation

Abstract

Cyclooxygenase-2 (COX-2) overexpression caused prolonged G 2 arrest after exposure to ionizing radiation (IR) in our previous study. We were therefore interested in investigating the function of COX-2 in the G 2 checkpoint pathway. Interestingly, we found that cells in which COX-2 is overexpressed showed up-regulated ataxia telangiectasia and Rad3 related (ATR) expression compared with control cells. In this study, we investigated the mechanism of ATR up-regulation by COX-2 and tested our hypothesis that COX-2-induced extracellular signal-regulated kinase (ERK) activation mediates up-regulation of ATR by COX-2. To investigate the relationship between COX-2 and ATR, we used two stable COX-2-overexpressing cancer cell lines (HCT116-COX-2 and H460-COX-2), a COX-2 knockdown A549 lung cancer cell line (AS), and an ATR knockdown HCT116 cell line. Cells were treated with various drugs [celecoxib, prostaglandin E 2 (PGE 2 ), PD98059, U0126, and hydroxyurea] and were then analyzed using reverse transcription-PCR, confocal microscopy, Western blotting, and clonogenic assay. COX-2-overexpressing cells were shown to have increased ERK phosphorylation and ATR expression compared with control cells, whereas AS cells were shown to have decreased levels of phospho-ERK and ATR. In addition, exogenously administered PGE 2 increased ERK phosphorylation. Inhibition of ERK phosphorylation decreased ATR expression in both HCT116-COX-2 and A549 cells. HCT116-COX-2 cells were resistant to IR or hydroxyurea compared with HCT116-Mock cells, whereas administration of ATR shRNA showed the opposite effect. COX-2 stimulates ERK phosphorylation via PGE 2 . This COX-2-induced ERK activation seems to increase ATR expression and activity in endogenous COX-2-overexpressing cancer cells as well as in COX-2-overexpressing stable cell

Gefitinib radiosensitizes non-small cell lung cancer cells through inhibition of ataxia telangiectasia mutated

“…Recently, we reported that COX-2 overexpressing cancer cells upregulate ataxia telangiectasia and rad3-related (ATR) expression and activity, and that upregulated ATR induces resistance to DNA damaging agents such as IR or hydroxyurea [39]. Therefore, upregulated ATR activity in COX-2 overexpressing cancer cells may compensate for the ATM activity inhibited by gefitinib, and thereby prevent MC.…”

Cooperative Enhancement of Radiosensitivity After Combined Treatment of 17-(Allylamino)-17-Demethoxygeldanamycin and Celecoxib in Human Lung and Colon Cancer Cell Lines

“…COX-2 is also known to be involved in carcinogenic processes through various pathways ). Therefore, COX-2 is also regarded as an important target molecule for cancer treatment as we previously reviewed ( Jun et al, 2009;Kim et al, 2009).…”

“…Research to identify these common target molecules will not be easy. However, we focused on molecules involved in the G 2 checkpoint, especially ATR and ATM, because we previously found that COX-2 profoundly prolongs IR-induced G 2 arrest and it is caused by upregulation of ATR by COX-2 (Shin et al, 2005; Kim et al, 2009). In addition, hsp90 also has many client proteins involved in cell cycle regulation, including Chk1, which is directly downstream of ATR.…”

Expression of COX-2 on Reed-Sternberg cells is an independent unfavorable prognostic factor in Hodgkin lymphoma treated with ABVD

“…In fact, COX-2 expression has been associated with several antiapoptotic pathways, such as induction of bcl-2 and subsequent survival mechanisms, or by induction of ATM and ATR in some solid tumors. 20 Furthermore, COX-2 has been associated with chemoresistance and radiation resistance by inducing neoangiogenesis and also because of its strong correlation with the expression of the MDR gene. 21 Nevertheless, the specific role of the COX-2 pathway in the pathogenesis of hematologic malignancies is not known.…”