Celecoxib Down-Regulates the Hypoxia-Induced Expression of HIF-1α and VEGF Through the PI3K/AKT Pathway in Retinal Pigment Epithelial Cells

Abstract

Background/Aims: The goal of this study was to detect the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in human retinal pigmented epithelial (RPE) cells treated with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, under hypoxic and normoxic conditions and to explore the signaling mechanism involved in regulating the hypoxia-induced expression of HIF-1α and VEGF in RPE cells. Methods: D407 cells were cultured in normoxic or hypoxic conditions, with or without celecoxib or a PI3K inhibitor (LY294002). The anti-proliferative effect of celecoxib was assessed using the MTT assay. RT-PCR, Western blotting and ELISA were performed to detect the levels of PI3K, phosphorylated AKT (p-AKT), HIF-1α, VEGF and COX-2. Results: Celecoxib inhibited the proliferation of RPE cells in a dose-dependent manner. Celecoxib suppressed the expression of VEGF at both the mRNA and protein levels and decreased HIF-1α protein expression. HIF-1α activation was regulated by the PI3K/AKT pathway. The celecoxib-induced down-regulation of HIF-1α and VEGF required the suppression of the hypoxia-induced PI3K/AKT pathway. However, the down-regulation of COX-2 did not occur in cells treated with celecoxib. Conclusions: The antiangiogenic effects of celecoxib in RPE cells under hypoxic conditions resulted from the inhibition of HIF-1α and VEGF expression, which may be partly mediated by a COX-2-independent, PI3K/AKT-dependent pathway.

Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze

“…Our study highlights that the capacity of celecoxib to aid repair in pAEC from children with wheeze is independent of COX2 inhibition. Unlike our findings, previous work in the oncology literature has suggested that celecoxib treatment of cancer cell lines may inhibit PI3K/Akt signaling at high micromolar concentrations (44,45). This discrepancy may highlight dose-dependent and cell-specific responses to celecoxib treatment in vitro.…”

Protective Effects of Fucoidan on Epithelial-Mesenchymal Transition of Retinal Pigment Epithelial Cells and Progression of Proliferative Vitreoretinopathy

“…The RPE, a monolayer of pigmented cells located between the nerve retina and Bruch’s membrane, is an important partner for the fit of the retina, and disturbance of the RPE may ultimately lead to retinal damage and disease. Various studies have investigated the relationship and underlying mechanism between the RPE and ocular diseases [19-21]. The RPE also participates in the pathogenesis of PVR.…”

Annexin A2 Promotes Development of Retinal Neovascularization through PI3K/ AKT Pathway

“…Therefore, the risk of intravitreal infection is much higher and some patients also respond poorly to anti-VEGF treatments [42] .Thus, identification of novel targets that play important roles in retinal neovascularization is urgently needed for those not responsible for anti-VEGF therapy [43] . Studies also demonstrated that celecoxib could inhibit the expression of VEGF and neovascularization growth in retinal pigment epithelial cells and the effect was mediated through a PI3K/AKT-dependent manner [44] and abrogating of VEGF significantly reduced the risk of developing to PDR in type 2 diabetes patients [45] .…”