Post-translational modifications of prostaglandin-endoperoxide synthase 2 in colorectal cancer: An update

Abstract

The biosynthesis of prostanoids is involved in both physiological and pathological processes. The expression of prostaglandin-endoperoxide synthase 2 (PTGS2; also known as COX-2) has been traditionally associated to the onset of several pathologies, from inflammation to cardiovascular, gastrointestinal and oncologic events. For this reason, the search of selective PTGS2 inhibitors has been a focus for therapeutic interventions. In addition to the classic non-steroidal anti-inflammatory drugs, selective and specific PTGS2 inhibitors, termed coxibs, have been generated and widely used. PTGS2 activity is less restrictive in terms of substrate specificity than the homeostatic counterpart PTGS1, and it accounts for the elevated prostanoid synthesis that accompanies several pathologies. The main regulation of PTGS2 occurs at the transcription level. In addition to this, the stability of the mRNA is finely regulated through the interaction with several cytoplasmic elements, ranging from specific microRNAs to proteins that control mRNA degradation. Moreover, the protein has been recognized to be the substrate for several post-translational modifications that affect both the enzyme activity and the targeting for degradation via proteasomal and non-proteasomal mechanisms. Among these modifications, phosphorylation, glycosylation and covalent modifications by reactive lipidic intermediates and by free radicals associated to the pro-inflammatory condition appear to be the main changes. Identification of these post-translational modifications is relevant to better understand the role of PTGS2 in several pathologies and to establish a correct analysis of the potential function of this protein in diseases progress. Finally, these modifications can be used as biomarkers to establish correlations with other parameters, including the immunomodulation dependent on molecular pathological epidemiology determinants, which may provide a better frame for potential therapeutic interventions.

Evaluation of Glycosylated PTGS2 in Colorectal Cancer for NSAIDS-Based Adjuvant Therapy

“…All patients underwent surgery as the first curative treatment. Tumors were located in the ascending (41), transverse (2), descending (17), sigmoid colon (19), and rectum (21), and they were staged as I (14), II (34), III (39), and IV (13) according to Union for International Cancer Control (UICC) 2009 classification.…”

“…Prostaglandin-endoperoxide synthase-2 (PTGS2), one of the key enzymes mediating prostaglandins neosynthesis, is typically induced by inflammatory stimuli and expressed by tumor epithelial cells in about 74-78% of colorectal cancer (CRC) (see [1] for review). PTGS2 exists both as a rapidly-degraded 68 kDa unglycosylated form, with increased catalytic activity, and a more stable, endoplasmic reticulum-associated, 72 kDa glycosylated form (gPTGS2) [2]. While unglycosylated PTGS2 can be detected in the normal mucosa, gPTGS2 is typically associated with CRC.…”

SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine

“…This is likely to reflect the complexity of the regulation of protein levels, which are determined by transcription and translation efficacy, factors that control mRNA stability (e.g. microRNAs and proteins that control mRNA degradation), and post-translational modifications that promote (proteasomal) protein degradation [Radhakrishnan and Green, 2016;Bicknell and Ricci, 2017;Dikic, 2017;Jaén et al, 2018;Ko and Dixon, 2018;Wolf and Menssen, 2018]. Moreover, mutations may affect SAMHD1 function, as demonstrated in patients with chronic lymphocytic leukaemia and colorectal cancer [Clifford et al, 2014;Rentoft et al, 2016].…”

Using BioPAX-Parser (BiP) to enrich lists of genes or proteins with pathway data

“…Hughes et al [ 101 ] describes the associations between “Metabolism of Proteins” pathway and the colorectal cancer. Jaén et al [ 102 ], Tomonaga et al [ 103 ] describe the role of “The Post-translational protein modification pathway” in the colorectal cancer. Fang et al [ 104 ] describes the “Cellular responses to external stimuli” as a general pathway that regulates how a single cell detects and responds to external molecular and physical signals, comprising the mitogen-activated protein kinases (MAPK), the extracellular-signal-regulated kinases in colorectal cancer.…”