Relationship between inflammation, COX-2 and EGFR (WP4483)

Homo sapiens

Arachidonic acid metabolic pathway can be activated by inflammation (stimulus). Arachidonic acid is released from membrane phospholipids by a phospholipase A2 (PLA-2) enzyme and converted to bioactive PGE-2 by COX-2. PGE2 induced transactivation of the EGFR by triggering Src and PGE2, an important regulator of CYP19A1 gene expression, stimulates CYP19A1 activity to increase localized estrogen 17-beta-estradiol (E2). The E2 binds to the classical ER to promote its dimerization and translocation to the nucleus where it modulates the expression of estrogen target genes (COX-2). The interaction of E2 with ER-alpha also activates signaling cascades that promote cell proliferation, such as the activation of c-Src tyrosine kinase (Src). Src activation stimulates a matrix metalloproteinase cascade that culminates in liberating the EGF. The free EGF ligand binds to EGFR family receptors that activates ERK signaling cascade. Cytosolic phospholipase A2 (cPLA) is a substrate for ERK and phosphorylation of cPLA (cPLAp), promoting its association with intracellular membranes such as those of the endoplasmic reticulum and mitochondria releasing lysophospholipids and arachidonic acid from these membranes. COX-2 catalyzes the conversion of arachidonic acid into PGE-2. These key molecules and pathways that connect chronic inflammation with inflammation-associated oncogenic transformation could be targeted by drugs or natural products for novel preventive and therapeutic strategies for malignant mesothelioma.


Laurent Winckers , Egon Willighagen , Anders Riutta , and Kristina Hanspers


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Homo sapiens



Pathway Ontology

arachidonic acid metabolic pathway


Label Type Compact URI Comment
Arachidonic acid Metabolite chebi:15843
E2 Metabolite chebi:606564
E2 Metabolite chebi:606564
E2 Metabolite chebi:606564
E2 Metabolite chebi:606564
E2 Metabolite chebi:606564
Arachidonic acid Metabolite chebi:15843
ESR1 GeneProduct ncbigene:2099
KRAS GeneProduct ncbigene:3845
NRAS GeneProduct ncbigene:4893
HRAS GeneProduct ncbigene:3265
PI3KB GeneProduct ncbigene:5291
PI3KD GeneProduct ncbigene:5293
PI3KG GeneProduct ncbigene:5294
AKT1 GeneProduct ncbigene:207
AKT2 GeneProduct ncbigene:208
AKT3 GeneProduct ncbigene:10000
ERK1 GeneProduct ncbigene:5595
ERK2 GeneProduct ncbigene:5594
CYP19A1 GeneProduct ncbigene:1588
PGE2 GeneProduct ncbigene:80142
BRAF GeneProduct ncbigene:673
PI3KA GeneProduct ncbigene:5290
COX-2 GeneProduct ncbigene:5743
EGFR GeneProduct ncbigene:1956
MMP1 GeneProduct ncbigene:4312
Src GeneProduct ncbigene:6714
ESR1 GeneProduct ncbigene:2099
ESR1 GeneProduct ncbigene:2099
PGE2 GeneProduct ncbigene:80142
cPLA GeneProduct ncbigene:51365
PTGER3 GeneProduct ncbigene:5733
PTGER2 GeneProduct ncbigene:5732
PTGER1 GeneProduct ncbigene:5731
PTGER4 GeneProduct ncbigene:5734
EGF Protein ncbiprotein:P01133


  1. Cyclooxygenase-2, epidermal growth factor receptor, and aromatase signaling in inflammation and mesothelioma. Nuvoli B, Galati R. Mol Cancer Ther. 2013 Jun;12(6):844–52. PubMed Europe PMC Scholia