Molecule Information

General Information of the Molecule (ID: Mol00557)

• Name: Prostaglandin G/H synthase 2 (PTGS2) ,Homo sapiens
• Synonyms: Cyclooxygenase-2; COX-2; PHS II; Prostaglandin H2 synthase 2; PGH synthase 2; PGHS-2; Prostaglandin-endoperoxide synthase 2; COX2
• Molecule Type: Protein
• Gene Name: PTGS2
• Gene ID: 5743
• Location: chr1:186671791-186680922[-]
• Sequence:
  MLARALLLCAVLALSHTANPCCSHPCQNRGVCMSVGFDQYKCDCTRTGFYGENCSTPEFL
  TRIKLFLKPTPNTVHYILTHFKGFWNVVNNIPFLRNAIMSYVLTSRSHLIDSPPTYNADY
  GYKSWEAFSNLSYYTRALPPVPDDCPTPLGVKGKKQLPDSNEIVEKLLLRRKFIPDPQGS
  NMMFAFFAQHFTHQFFKTDHKRGPAFTNGLGHGVDLNHIYGETLARQRKLRLFKDGKMKY
  QIIDGEMYPPTVKDTQAEMIYPPQVPEHLRFAVGQEVFGLVPGLMMYATIWLREHNRVCD
  VLKQEHPEWGDEQLFQTSRLILIGETIKIVIEDYVQHLSGYHFKLKFDPELLFNKQFQYQ
  NRIAAEFNTLYHWHPLLPDTFQIHDQKYNYQQFIYNNSILLEHGITQFVESFTRQIAGRV
  AGGRNVPPAVQKVSQASIDQSRQMKYQSFNEYRKRFMLKPYESFEELTGEKEMSAELEAL
  YGDIDAVELYPALLVEKPRPDAIFGETMVEVGAPFSLKGLMGNVICSPAYWKPSTFGGEV
  GFQIINTASIQSLICNNVKGCPFTSFSVPDPELIKTVTINASSSRSGLDDINPTVLLKER
  STEL
• Function: Dual cyclooxygenase and peroxidase in the biosynthesis pathway of prostanoids, a class of C20 oxylipins mainly derived from arachidonate, with a particular role in the inflammatory response. The cyclooxygenase activity oxygenates arachidonate (AA, C20:4(n-6)) to the hydroperoxy endoperoxide prostaglandin G2 (PGG2), and the peroxidase activity reduces PGG2 to the hydroxy endoperoxide PGH2, the precursor of all 2-series prostaglandins and thromboxanes. This complex transformation is initiated by abstraction of hydrogen at carbon 13 (with S-stereochemistry), followed by insertion of molecular O2 to form the endoperoxide bridge between carbon 9 and 11 that defines prostaglandins. The insertion of a second molecule of O2 (bis-oxygenase activity) yields a hydroperoxy group in PGG2 that is then reduced to PGH2 by two electrons. Similarly catalyzes successive cyclooxygenation and peroxidation of dihomo-gamma-linoleate (DGLA, C20:3(n-6)) and eicosapentaenoate (EPA, C20:5(n-3)) to corresponding PGH1 and PGH3, the precursors of 1- and 3-series prostaglandins. In an alternative pathway of prostanoid biosynthesis, converts 2-arachidonoyl lysophopholipids to prostanoid lysophopholipids, which are then hydrolyzed by intracellular phospholipases to release free prostanoids. Metabolizes 2-arachidonoyl glycerol yielding the glyceryl ester of PGH2, a process that can contribute to pain response. Generates lipid mediators from n-3 and n-6 polyunsaturated fatty acids (PUFAs) via a lipoxygenase-type mechanism. Oxygenates PUFAs to hydroperoxy compounds and then reduces them to corresponding alcohols. Plays a role in the generation of resolution phase interaction products (resolvins) during both sterile and infectious inflammation. Metabolizes docosahexaenoate (DHA, C22:6(n-3)) to 17R-HDHA, a precursor of the D-series resolvins (RvDs). As a component of the biosynthetic pathway of E-series resolvins (RvEs), converts eicosapentaenoate (EPA, C20:5(n-3)) primarily to 18S-HEPE that is further metabolized by ALOX5 and LTA4H to generate 18S-RvE1 and 18S-RvE2. In vascular endothelial cells, converts docosapentaenoate (DPA, C22:5(n-3)) to 13R-HDPA, a precursor for 13-series resolvins (RvTs) shown to activate macrophage phagocytosis during bacterial infection. In activated leukocytes, contributes to oxygenation of hydroxyeicosatetraenoates (HETE) to diHETES (5,15-diHETE and 5,11-diHETE). During neuroinflammation, plays a role in neuronal secretion of specialized preresolving mediators (SPMs) 15R-lipoxin A4 that regulates phagocytic microglia.
• Uniprot ID: PGH2_HUMAN
• Ensembl ID: ENSG00000073756
• HGNC ID: HGNC:9605

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Aspirin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Hypo-attenuated leaflet thickening [1]

• Resistant Disease: Hypo-attenuated leaflet thickening [ICD-11: BD10.2]
• Resistant Drug: Aspirin
• Molecule Alteration: SNP; rs20417
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: We thoroughly genotyped 34 SNPs and 8 SNPs that have been reported for clopidogrel and aspirin resistance. A total of 148 patients were enrolled. There were 15 patients demonstrating signs of HALT. Patients with HALT had a higher rate of atrial fibrillation (AF) pre-TAVR (33.3 vs. 7.5%, P = 0.01).

Disease Class: Dysmenorrhea [2]

• Resistant Disease: Dysmenorrhea [ICD-11: GA34.3]
• Resistant Drug: Aspirin
• Molecule Alteration: SNP; rs20417
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: Notably, rs20417 is a SNP in the promoter region of COX-2 associated with aspirin resistance. Further research is needed to determine if the identified SNP have a transcriptional effect contributing to NSAID-resistant dysmenorrhea.

Celecoxib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioblastoma [3]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Sensitive Drug: Celecoxib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: MDA-175 cells; Pleural effusion; Homo sapiens (Human); CVCL_1400
• In Vitro Model: MMQ cells; Pituitary gland; Rattus norvegicus (Rat); CVCL_2117
• Experiment for Molecule Alteration: Western blot analysis; Fluorescence microscopy assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay; Fluorescence-activated cell sorting (FACS) assay; Flow cytometry
• Mechanism Description: Celecoxib reverses the glioblastoma chemo-resistance to temozolomide through mitochondrial metabolism.

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Bladder cancer [4]

• Sensitive Disease: Bladder cancer [ICD-11: 2C94.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: T24 cells; Bladder; Homo sapiens (Human); CVCL_0554
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Enforced expression of miR-101 enhances cisplatin sensitivity in human bladder cancer cells by downregulating the cyclooxygenase-2 pathway.

Fotemustine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Endometriosis [5]

• Resistant Disease: Endometriosis [ICD-11: GA10.0]
• Resistant Drug: Fotemustine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vivo Model: Female Sprague-Dawley rats model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: Fotemustine and dexamethasone administration had anti-apoptotic activity, restoring the impaired mechanism (TUNEL assay and Western blot analysis of Bax and Bcl-2). Moreover, no gastric disfunction was detected (histological analysis of stomachs). Thus, our data showed that the combined therapy of fotemustine and dexamethasone reduced endometriosis-induced inflammation, hyperproliferation and apoptosis resistance.

Irinotecan

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Colorectal cancer [6]

• Sensitive Disease: Colorectal cancer [ICD-11: 2B91.1]
• Sensitive Drug: Irinotecan
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Sphere tumorogenicity; Inhibition; hsa04140
• Cell Pathway Regulation: Wnt signaling pathway; Inhibition; hsa04310
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: LS513 cells; Colon; Homo sapiens (Human); CVCL_1386
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: COX-2 allows Wnt activation, which is essential for CSC growth, the decrease of colorectal CSC formation and growth could result from miR-451-mediated downregulation of cyclooxygenase-2 (COX-2) and Wnt pathway.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Brain cancer [ICD-11: 2A00]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Nervous tissue
• The Specified Disease: Brain cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.47E-01; Fold-change: -1.46E-01; Z-score: -1.42E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.58E-02; Fold-change: 3.46E-01; Z-score: 1.66E+00
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.74E-01; Fold-change: 2.26E-01; Z-score: 1.78E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Neuroectodermal tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.91E-03; Fold-change: -1.71E+00; Z-score: -1.72E+00

Bladder cancer [ICD-11: 2C94]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Bladder tissue
• The Specified Disease: Bladder cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.95E-02; Fold-change: 6.63E-01; Z-score: 7.42E-01

ICD Disease Classification 16

Endometriosis [ICD-11: GA10]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Endometrium
• The Specified Disease: Endometriosis
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.40E-01; Fold-change: -9.05E-01; Z-score: -5.03E-01

References

• Ref 1: Gene polymorphisms in dual antiplatelet therapy and the presence of hypo-attenuated leaflet thickening after transcatheter aortic valve replacement .J Thromb Thrombolysis. 2018 Apr;45(3):463-465. doi: 10.1007/s11239-018-1636-z. 10.1007/s11239-018-1636-z
• Ref 2: Nonsteroidal antiinflammatory drug resistance in dysmenorrhea: epidemiology, causes, and treatment .Am J Obstet Gynecol. 2018 Apr;218(4):390-400. doi: 10.1016/j.ajog.2017.08.108. Epub 2017 Sep 6. 10.1016/j.ajog.2017.08.108
• Ref 3: Celecoxib reverses the glioblastoma chemo-resistance to temozolomide through mitochondrial metabolism .Aging (Albany NY). 2021 Sep 8;13(17):21268-21282. doi: 10.18632/aging.203443. Epub 2021 Sep 8. 10.18632/aging.203443
• Ref 4: Enforced expression of miR-101 enhances cisplatin sensitivity in human bladder cancer cells by modulating the cyclooxygenase-2 pathway. Mol Med Rep. 2014 Oct;10(4):2203-9. doi: 10.3892/mmr.2014.2455. Epub 2014 Aug 6.
• Ref 5: Regulation of Inflammatory and Proliferative Pathways by Fotemustine and Dexamethasone in Endometriosis .Int J Mol Sci. 2021 Jun 1;22(11):5998. doi: 10.3390/ijms22115998. 10.3390/ijms22115998
• Ref 6: MicroRNA-451 is involved in the self-renewal, tumorigenicity, and chemoresistance of colorectal cancer stem cells. Stem Cells. 2011 Nov;29(11):1661-71. doi: 10.1002/stem.741.