Relationship between inflammation, COX-2 and EGFR (Homo sapiens)

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1PLA-2StimulusNucleusDNAEGFPI3KAAKT1CYP19A1Arachidonic acidSrcERK2AKT2PI3KBAKT3EGFRMMP1ERK1BRAFCOX-2ESR1PI3KDPI3KGKRASHRASNRASPGE2E2ESR1E2E2E2ESR1E2PGE2cPLAPTGER3PTGER2PTGER1PTGER4Arachidonic acid


Description

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.

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Bibliography

  1. Nuvoli B, Galati R; ''Cyclooxygenase-2, epidermal growth factor receptor, and aromatase signaling in inflammation and mesothelioma.''; Mol Cancer Ther, 2013 PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
107172view14:25, 17 September 2019MaintBotChEBI identifier normalization
102457view16:03, 23 December 2018AriuttaOntology Term : 'arachidonic acid metabolic pathway' added !
102321view08:18, 20 December 2018EgonwModified title
102285view14:15, 17 December 2018LaurentCorrected metabolite types
102284view13:41, 17 December 2018LaurentModified description
102283view13:37, 17 December 2018LaurentModified description
102282view13:16, 17 December 2018LaurentChanged enzyme
102281view13:15, 17 December 2018LaurentNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AKT1GeneProduct207 (Entrez Gene)
AKT2GeneProduct208 (Entrez Gene)
AKT3GeneProduct10000 (Entrez Gene)
Arachidonic acidMetaboliteCHEBI:15843 (ChEBI)
BRAFGeneProduct673 (Entrez Gene)
COX-2GeneProduct5743 (Entrez Gene)
CYP19A1GeneProduct1588 (Entrez Gene)
E2MetaboliteCHEBI:606564 (ChEBI)
EGFProteinP01133 (NCBI Protein)
EGFRGeneProduct1956 (Entrez Gene)
ERK1GeneProduct5595 (Entrez Gene)
ERK2GeneProduct5594 (Entrez Gene)
ESR1GeneProduct2099 (Entrez Gene)
HRASGeneProduct3265 (Entrez Gene)
KRASGeneProduct3845 (Entrez Gene)
MMP1GeneProduct4312 (Entrez Gene)
NRASGeneProduct4893 (Entrez Gene)
PGE2GeneProduct80142 (Entrez Gene)
PI3KAGeneProduct5290 (Entrez Gene)
PI3KBGeneProduct5291 (Entrez Gene)
PI3KDGeneProduct5293 (Entrez Gene)
PI3KGGeneProduct5294 (Entrez Gene)
PTGER1GeneProduct5731 (Entrez Gene)
PTGER2GeneProduct5732 (Entrez Gene)
PTGER3GeneProduct5733 (Entrez Gene)
PTGER4GeneProduct5734 (Entrez Gene)
SrcGeneProduct6714 (Entrez Gene)
cPLAGeneProduct51365 (Entrez Gene)

Annotated Interactions

No annotated interactions

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