Glycosylation of human cyclooxygenase-2 (COX-2) decreases the efficacy of certain COX-2 inhibitors

Abstract

Prostanoids play an important role in a variety of physiological and pathophysiological processes including inflammation and cancer. The rate-limiting step in the prostanoid biosynthesis pathway is catalyzed by cyclooxygenase-2 (COX-2). COX-2 exists as two glycoforms, 72 and 74 kDa, the latter resulting from an additional glycosylation at Asn(580). In this study, Asn(580) was mutated, and the mutant and wild-type COX-2 genes were expressed in COS-1 cells to determine how glycosylation affects the inhibition of COX-2 activity by aspirin, flurbiprofen, ibuprofen, celecoxib, and etoricoxib. Results indicate that certain inhibitors were 2-5 times more effective at inhibiting COX-2 activity when the glycosylation site was eliminated, indicating that glycosylation of COX-2 at Asn(580) decreases the efficacy of some inhibitors.

Expression of cyclo‐oxygenases‐1 and ‐2, and microsomal prostaglandin E synthase‐1 in penile and preputial papillomas and squamous cell carcinomas in the horse

“…Normal weight mPGES‐1 is about 17 kDA, and the additional band may reflect a post translational modification (glycosylation) of the protein, which may be responsible for the intense IHC staining in the site‐matched control tissue. Similarly, multiple glycoforms of human COX‐2 (70‐, 72‐, 74 kDA) have been reported . Antibody cross reaction with a cytosolic PGES may be another explanation for the intense staining in normal skin.…”

Protein Glycosylation and Tumor Microenvironment Alterations Driving Cancer Hallmarks

“…Moreover, several inflammatory mediators are regulated by its glycosylation state. Namely, NF-κB is activated by O -GlcNAcylation at Ser350 of its c-Rel subunit (254), while the proinflammatory cytokine Cyclooxygenase-2 (COX-2) turnover depends on Asn570 glycosylation, negatively affecting the efficacy of certain COX-2 inhibitors (255, 256). Furthermore, recent studies have described that non-human N -glycolyl-neuraminic acid (Neu5Gc) can be incorporated into cell surface glycans instead of N -acetyl-neuraminic acid (Neu5Ac), leading to autoimmune systemic inflammation associated with cancer initiation and progression (257–259).…”

Hallmarks of glycosylation in cancer

“…The transcriptional activity of NF-κB can be regulated by O-GlcNAcylation [139], which is known to be upregulated in multiple cancer types [45]. Similarly, the pro-inflammatory molecule COX2 is also regulated by glycosylation [140], and the efficiency of some COX2 inhibitors is thought to be dependent on COX2 glycosylation state [141]. Interestingly, a diet derived sialic acid called N-glycolylneuraminic acid (Neu5Gc, found primarily in red meat) can be incorporated in human tissues.…”