Cyclooxygenase 2: protein-protein interactions and posttranslational modifications

Abstract

Numerous studies implicate the cyclooxygenase 2 (COX2) enzyme and COX2-derived prostanoids in various human diseases, and thus, much effort has been made to uncover the regulatory mechanisms of this enzyme. COX2 has been shown to be regulated at both the transcriptional and posttranscriptional levels, leading to the development of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX2 inhibitors (COXIBs), which inhibit the COX2 enzyme through direct targeting. Recently, evidence of posttranslational regulation of COX2 enzymatic activity by s-nitrosylation, glycosylation, and phosphorylation has also been presented. Additionally, posttranslational regulators that actively downregulate COX2 expression by facilitating increased proteasome degradation of this enzyme have also been reported. Moreover, recent data identified proteins, located in close proximity to COX2 enzyme, that serve as posttranslational modulators of COX2 function, upregulating its enzymatic activity. While the precise mechanisms of the protein-protein interaction between COX2 and these regulatory proteins still need to be addressed, it is likely these interactions could regulate COX2 activity either as a result of conformational changes of the enzyme or by impacting subcellular localization of COX2 and thus affecting its interactions with regulatory proteins, which further modulate its activity. It is possible that posttranslational regulation of COX2 enzyme by such proteins could contribute to manifestation of different diseases. The uncovering of posttranslational regulation of COX2 enzyme will promote the development of more efficient therapeutic strategies of indirectly targeting the COX2 enzyme, as well as provide the basis for the generation of novel diagnostic tools as biomarkers of disease.

The next‐generation BET inhibitor, PLX51107, delays melanoma growth in a CD8‐mediated manner

“…Additionally, we observed a reduction in the expression of IL‐6 and CD62E in D4M3.A cells treated in vitro (Figure A), transcripts known to decrease in Cox2‐deficient melanomas (Zelenay et al, ). Interestingly, transcript levels of Cox2 (ptgs2) were unaltered during BETi treatment, suggesting post‐translational degradation of Cox2 (Alexanian & Sorokin, ; Figure A). Together, these data suggest that PLX51107 decreases Cox2 expression and causes influx of activated DCs in the tumor microenvironment.…”

“…It remains unclear how PLX51107 modulates Cox2 expression. Cox2 transcript levels remain unchanged during BETi, and Cox2 has previously been shown to be proteasomally degraded after ubiquitylation (Alexanian & Sorokin, ). Determining if BETi induce Cox2 post‐translational modifications and subsequent degradation requires further study.…”

Nitrodi thermal water downregulates protein S‑nitrosylation in RKO cells

“…The S-nitrosylation of COX-2 negatively regulates its enzymatic activity ( 37 , 38 ). In the present study, following immunostaining and autoradiography, the COX-2 antibody recognized a light form of approximately 70 kDa (COX-L) and another isoform of approximately 72 kDa attributable to the S-nitrosylated active form (COX-H).…”

Interplay between post-translational cyclooxygenase-2 modifications and the metabolic and proteomic profile in a colorectal cancer cohort

“…The potential tumor suppressor enzyme 15-prostaglandin dehydrogenase (15-PGDH), which catalyzes the degradation of PGE 2 , is usually down-regulated in colorectal adenoma and carcinoma cells[8,9]. In addition to this, experimental data have demonstrated that, not only the expression levels of COX-2 are important: post-translational modifications of this enzyme may also regulate its function and degradation[10]. COX-2 sequence contains five potential N-glycosylation sites, three of which are always glycosylated, one Asn580 in human and mouse that is glycosylated ≤ 50% of the times, and one that is never glycosylated[11].…”