Glucocorticoids suppress hypoxia‐induced COX‐2 and hypoxia inducible factor‐1α expression through the induction of glucocorticoid‐induced leucine zipper

Abstract

BACKGROUND AND PURPOSEThe COX-2/PGE2 pathway in hypoxic cancer cells has important implications for stimulation of inflammation and tumourigenesis. However, the mechanism by which glucocorticoid receptors (GRs) inhibit COX-2 during hypoxia has not been elucidated. Hence, we explored the mechanisms underlying glucocorticoid-mediated inhibition of hypoxia-induced COX-2 in human distal lung epithelial A549 cells. EXPERIMENTAL APPROACHThe expressions of COX-2 and glucocorticoid-induced leucine zipper (GILZ) in A549 cells were determined by Western blot and/or quantitative real time-PCR respectively. The anti-invasive effect of GILZ on A549 cells was evaluated using the matrigel invasion assay. KEY RESULTSThe hypoxia-induced increase in COX-2 protein and mRNA levels and promoter activity were suppressed by dexamethasone, and this effect of dexamethasone was antagonized by the GR antagonist RU486. Overexpression of GILZ in A549 cells also inhibited hypoxia-induced COX-2 expression levels and knockdown of GILZ reduced the glucocorticoid-mediated inhibition of hypoxia-induced COX-2 expression, indicating that the inhibitory effects of dexamethasone on hypoxia-induced COX-2 are mediated by GILZ. GILZ suppressed the expression of hypoxia inducible factor (HIF)-1α at the protein level and affected its signalling pathway. Hypoxia-induced cell invasion was also dramatically reduced by GILZ expression. CONCLUSION AND IMPLICATIONSDexamethasone-induced upregulation of GILZ not only inhibits the hypoxic-evoked induction of COX-2 expression and cell invasion but further blocks the HIF-1 pathway by destabilizing HIF-1α expression. Taken together, these findings suggest that the suppression of hypoxia-induced COX-2 by glucocorticoids is mediated by GILZ. Hence, GILZ is a potential key therapeutic target for suppression of inflammation under hypoxia. AbbreviationsGILZ, glucocorticoid-induced leucine zipper; GR, glucocorticoid receptor; HIF, hypoxia-inducible factor

Electrophilic Lipid Mediator 15-Deoxy-Δ12,14-Prostaglandin J2 Modifies Glucocorticoid Signaling via Receptor SUMOylation

“…HIF1A belongs to the hypoxia-inducible factor family that plays a critical role in hypoxic stress (44,45). SUMOylation can also modulate the HIF1A action during hypoxia (46,47), and glucocorticoids are capable of suppressing HIF1A expression through the induction of glucocorticoid-induced leucine zipper (48).…”

Hypoxia-induced force increase (HIFI) is a novel mechanism underlying the strengthening of labor contractions, produced by hypoxic stresses

“…Prostaglandin F2α (PGF2α), like oxytocin, is a major stimulator of uterine activity in labor (22). Hypoxia has been shown to up-regulate COX2 and increase prostaglandin production in smooth muscle and other tissues (23,24), and this has been hypothesized to contribute to labor (25). We therefore investigated the effects of inhibiting prostaglandin biosynthesis on HIFI by blocking the cyclo-oxygenases.…”

Red ginseng represses hypoxia-induced cyclooxygenase-2 through sirtuin1 activation

“…Glucocorticoid strongly suppresses COX-2 expression induced by inflammatory stimuli (Lim et al 2014;Yang et al 2008). To assess the involvement of the well-known anti-inflammatory glucocorticoid receptor (GR) pathway in the KRG-WE inhibition of hypoxia induced COX-2 in A549 cells, we pre-incubated cells with the GR antagonist RU486 for 1 h and co-treated with hypoxia.…”

“…Recently, we reported glucocorticoid-induced leucine zipper (GILZ) plays a major role in suppression of hypoxia-induced COX-2 (Lim et al 2014). It suggested that GILZ is an important molecular therapeutic target for the inflammatory response and tumorigenesis in lung cancer.…”