Prostaglandin and leukotriene metabolism in senescence (Homo sapiens)

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52965666699596595995656676575StressEP2 (extracellular)PTGESRASCytosolic phospholipase A2TXA2Membrane phospholipidsROSPGH2PGE2PGG2PTGDSArachidonic acidcAMPdihomo-15d-PGJ2PGD2GsSenescenceIGFBP5COX-1p38 MAPKAdrenic acidAdenylate Cyclase15d-PGJ2Cytosolic phospholipase A2PLCPGI25COX-2PGD SynthasePGE SynthasePGI SynthaseTxA SynthasePGF SynthasePGF2alphaEP1 (extracellular)EP3 (extracellular)EP4 (extracellular)GiGq666Adenylate CyclasecAMPP3314, 109442, 4322242, 1048941043121011182ALOX5APCa2+ALOX5LTC4SLTA4HALOX15Bp21LTB45-HPETELTD4p53RB1ALOX15LTA4LTE4LTC4SIRT1ALOX12CysLT1Rp53PRB1PSenescenceCa2+p53SASP?6


Prostaglandins are active lipid molecules that are shown to have a great impact on cellular senescence (Wiley et al., 2021). Prostaglandins are derived from arachidonic acid, which is cleaved by the enzyme cytosolic phospholipase A2 (cPLA2) from the membrane phospholipids (Yang et al., 2011).

The cyclooxygenase 2 (COX-2)-prostaglandin E2 (PGE2) pathway takes part in the induction, as well as the maintenance of senescence. COX-2 is the inducing enzyme which causes the conversion of AA into PGH2 and PGG2, which are then readily converted into PGF2⍺, PGD2, PGE2, PGI2, and TxA2 through prostaglandin synthases (Cormenier et al., 2017; Martien et al., 2013). The produced active prostaglandins can then act on intracellular receptors and trigger a downward signalling cascade, leading to the stimulation or inhibition of cAMP or the stimulation of Ca2+. The cAMP-dependent pathway leads to the stimulation of the insulin-like growth factor binding protein 5 (IGFBP5) production, which then also activates p53. P53 activation reinforces senescence by stimulating the expression of COX mRNA, thus creating a positive feedback loop (Yang et al., 2011).

Two important active prostaglandins, namely dihomo-15d-PGJ2 and 15d-PGJ2 are highly elevated in senescent cells and induce COX-1 and 2, PTGES and PTGDS production through the activation of RAS and subsequently p53, reinforcing the positive feedback loop. Dihomo-15d-PGJ2 is the most highly elevated senescence-associated prostaglandin and is produced by the elongation of arachidonic acid into adrenic acid, which is then enzymatically converted to yield the prostaglandin. 15d-PGJ2 on the other hand is produced through the dehydration of the active prostaglandin PGD2. In addition, RAS stimulates the secretion of SASP factors, which can consequently affect surrounding cells (Wiley et al., 2021).

Leukotrienes play an important role in the pathogenesis of inflammation. Just like prostaglandins, leukotrienes are synthesized from arachidonic acid that was cleaved from the membrane phospholipids (Wiley et al., 2019). ALOX12, ALOX15, ALOX5AP, LTC4S, LTA4H, ALOX15B and ALOX5, which are enzymes that conversion of arachidonic acid to either leukotriene A4 (LT4A) or Arachidonic acid 5-hydroperoxide (5-HPETE), are upregulated in senescence (Wiley et al., 2019; Häfner et al., 2019). The produced LTA4 can be converted into LTB4 or LTC4. LTC4 can then be consecutively cleaved into LTD4 and LTE4 (Suryadevara et al., 2020). All the mentioned leukotrienes are increased in cellular senescence and are thought to be part of the SASP (Lin & Xu, 2020).

LTD4 is of particular importance in cellular senescence due to its increased interaction with the cysteinyl leukotriene receptor 1 (CysLT1R) (Wei et al., 2018; Song et al., 2019). This interaction has various consequences, such as the release of intracellular Ca2+, an increase of p21 and it also inhibits sirtuin 1 (SIRT1). SIRT1 regulates the cell cycle by inhibiting the phosphorylation of p53 and the release of various cytokines (Wei et al., 2018). Therefore, it increases the release of pro-inflammatory cytokines and induce cellular senescence via the activation of p53 (Song et al., 2019).

ALOX5 contributes to an increase in reactive oxygen species (ROS) (Catalano et al., 2005; Menna et al., 2010). These ROS are thought to activate p53 which binds to ALOX5 and further increases its action (Häfner et al., 2019). Moreover, ALOX5 uses Ca2+ as a cofactor and its increased intracellular concentration further promotes ALOX5's action (Menna et al., 2010). LTB4 is also stimulates the production of ROS. ALOX5 then stimulates the phosphorylation of p53 and activates p21 (Menna et al., 2010; Catalano et al., 2005). This then causes the dephosphorylation of the retinoblastoma protein (RB1). As a consequence, senescence is induced (Catalano et al., 2005).

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  1. Lin Y, Xu Z; ''Fibroblast Senescence in Idiopathic Pulmonary Fibrosis.''; Front Cell Dev Biol, 2020 PubMed Europe PMC Scholia
  2. Wei J, Chen S, Guo W, Feng B, Yang S, Huang C, Chu J; ''Leukotriene D4 induces cellular senescence in osteoblasts.''; Int Immunopharmacol, 2018 PubMed Europe PMC Scholia
  3. Suryadevara V, Ramchandran R, Kamp DW, Natarajan V; ''Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways.''; Int J Mol Sci, 2020 PubMed Europe PMC Scholia
  4. Catalano A, Rodilossi S, Caprari P, Coppola V, Procopio A; ''5-Lipoxygenase regulates senescence-like growth arrest by promoting ROS-dependent p53 activation.''; EMBO J, 2005 PubMed Europe PMC Scholia
  5. Wiley CD, Sharma R, Davis SS, Lopez-Dominguez JA, Mitchell KP, Wiley S, Alimirah F, Kim DE, Payne T, Rosko A, Aimontche E, Deshpande SM, Neri F, Kuehnemann C, Demaria M, Ramanathan A, Campisi J; ''Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis.''; Cell Metab, 2021 PubMed Europe PMC Scholia
  6. Cormenier J, Martin N, Deslé J, Salazar-Cardozo C, Pourtier A, Abbadie C, Pluquet O; ''The ATF6α arm of the Unfolded Protein Response mediates replicative senescence in human fibroblasts through a COX2/prostaglandin E2intracrine pathway.''; Mech Ageing Dev, 2018 PubMed Europe PMC Scholia
  7. Yang HH, Kim C, Jung B, Kim KS, Kim JR; ''Involvement of IGF binding protein 5 in prostaglandin E(2)-induced cellular senescence in human fibroblasts.''; Biogerontology, 2011 PubMed Europe PMC Scholia
  8. Häfner AK, Kahnt AS, Steinhilber D; ''Beyond leukotriene formation-The noncanonical functions of 5-lipoxygenase.''; Prostaglandins Other Lipid Mediat, 2019 PubMed Europe PMC Scholia
  9. Wiley CD, Brumwell AN, Davis SS, Jackson JR, Valdovinos A, Calhoun C, Alimirah F, Castellanos CA, Ruan R, Wei Y, Chapman HA, Ramanathan A, Campisi J, Jourdan Le Saux C; ''Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis.''; JCI Insight, 2019 PubMed Europe PMC Scholia
  10. Menna C, Olivieri F, Catalano A, Procopio A; ''Lipoxygenase inhibitors for cancer prevention: promises and risks.''; Curr Pharm Des, 2010 PubMed Europe PMC Scholia


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119484view08:41, 2 July 2021EgonwUpdated data source so that link out work.
119438view07:46, 29 June 2021DKalbeDescription prostaglandins
119423view17:57, 28 June 2021JDoreenReferences
119416view12:11, 28 June 2021JDoreenAdded references and state
119412view09:59, 28 June 2021DKalbeChanging an arrow
119411view09:31, 28 June 2021JDoreenCorrections
119410view06:58, 28 June 2021DKalbeFixing interactions and description
119390view10:02, 27 June 2021JDoreenAnnotations
119380view12:00, 25 June 2021DKalbeDescription leukotrienes
119376view11:33, 25 June 2021TadeIdowuAnnotation
119374view10:46, 25 June 2021EweitzOntology Term : 'aging pathway' added !
119373view10:41, 25 June 2021EweitzOntology Term : 'leukotriene metabolic pathway' added !
119372view10:40, 25 June 2021EweitzOntology Term : 'prostaglandin metabolic pathway' added !
119369view10:34, 25 June 2021EweitzModified title
119354view19:28, 24 June 2021JDoreenAnnotations.
119353view14:14, 24 June 2021Aysegul CelikModified title
119343view10:05, 24 June 2021DKalbeData node
119342view09:56, 24 June 2021DKalbeData nodes
119341view09:49, 24 June 2021DKalbeData nodes
119340view09:33, 24 June 2021DKalbeData nodes
119339view09:17, 24 June 2021DKalbeReferences
119331view15:48, 23 June 2021JDoreenAnnotations
119326view15:14, 23 June 2021JDoreenArrows and boxes.
119322view14:43, 23 June 2021JDoreenModified description
119321view14:28, 23 June 2021JDoreenp53 and ROS.
119320view13:47, 23 June 2021JDoreenChanged anchoring of some arrows and some boxes. Added shape to pathways.
119302view13:03, 23 June 2021Frucsek13Modified title
119299view11:45, 23 June 2021TadeIdowuP38 MAPK
119298view11:39, 23 June 2021TadeIdowuRAS Protein
119297view11:30, 23 June 2021TadeIdowuAnnotation & Arrows
119295view11:24, 23 June 2021TadeIdowuAnnotation
119228view18:42, 22 June 2021DKalbemodifying references
119225view18:35, 22 June 2021DKalbeAddition of leukotriene metabolism pathway
119220view16:30, 22 June 2021TadeIdowuAddition of Phsophorylation and Annotation
119214view14:41, 22 June 2021Mario5181Modified title
119213view14:41, 22 June 2021Mario5181Modified title
119212view14:20, 22 June 2021JDoreenNew pathway

External references


View all...
NameTypeDatabase referenceComment
15d-PGJ2MetaboliteCHEBI:34159 (ChEBI)
5-HPETEMetaboliteHMDB11135 (HMDB)
ALOX12GeneProductENSG00000108839 (Ensembl)
ALOX15BGeneProductENSG00000179593 (Ensembl)
ALOX15GeneProductENSG00000161905 (Ensembl)
ALOX5APGeneProductENSG00000132965 (Ensembl)
ALOX5GeneProductENSG00000012779 (Ensembl)
Adenylate CyclaseProteinA0A0A0MSC1 (Uniprot-TrEMBL)
Adrenic acidMetaboliteCHEBI:53487 (ChEBI)
Arachidonic acidMetaboliteHMDB01043 (HMDB)
COX-1GeneProductENSG00000095303 (Ensembl)
COX-2GeneProductENSG00000073756 (Ensembl)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
CysLT1RProteinQ9Y271 (Uniprot-TrEMBL)
Cytosolic phospholipase A2ProteinP47712 (Uniprot-TrEMBL)
EP1 (extracellular)GeneProductENSG00000160951 (Ensembl)
EP2 (extracellular)GeneProductENSG00000125384 (Ensembl)
EP3 (extracellular)GeneProductENSG00000050628 (Ensembl)
EP4 (extracellular)GeneProductENSG00000171522 (Ensembl)
GiGeneProductENSG00000127955 (Ensembl)
GqGeneProductENSG00000156052 (Ensembl)
GsGeneProductENSG00000087460 (Ensembl)
IGFBP5GeneProductENSG00000115461 (Ensembl)
LTA4MetaboliteCHEBI:15651 (ChEBI)
LTA4HGeneProductENSG00000111144 (Ensembl)
LTB4MetaboliteCHEBI:15647 (ChEBI)
LTC4MetaboliteCHEBI:16978 (ChEBI)
LTC4SGeneProductENSG00000213316 (Ensembl)
LTD4MetaboliteCHEBI:28666 (ChEBI)
LTE4MetaboliteCHEBI:15650 (ChEBI)
Membrane phospholipidsMetaboliteCHEBI:16247 (ChEBI)
PGD SynthaseGeneProductENSG00000107317 (Ensembl)
PGD2MetaboliteCHEBI:15555 (ChEBI)
PGE SynthaseGeneProductPTGES (HGNC)
PGE2MetaboliteCHEBI:15551 (ChEBI)
PGF SynthaseGeneProductQ8TBF2 (Uniprot-TrEMBL)
PGF2alphaMetaboliteCHEBI:15553 (ChEBI)
PGG2MetaboliteCHEBI:27647 (ChEBI)
PGH2MetaboliteCHEBI:15554 (ChEBI)
PGI SynthaseGeneProductENSG00000124212 (Ensembl)
PGI2MetaboliteCHEBI:15552 (ChEBI)
PLCProteinA0A087WT80 (Uniprot-TrEMBL)
PTGDSGeneProductENSG00000107317 (Ensembl)
PTGESGeneProductENSG00000148344 (Ensembl)
RASProteinP01112 (Uniprot-TrEMBL)
RB1GeneProductENSG00000139687 (Ensembl)
ROSMetabolite26523 (ChEBI)
SASPPathwayWP3391 (WikiPathways)
SIRT1GeneProductENSG00000096717 (Ensembl)
SenescencePathwayWP615 (WikiPathways)
TXA2MetaboliteCHEBI:15627 (ChEBI)
TxA SynthaseGeneProductENSG00000059377 (Ensembl)
cAMPMetaboliteHMDB00058 (HMDB)
dihomo-15d-PGJ2Metabolite16061095 (PubChem-compound)
p21ProteinA0A024RCX5 (Uniprot-TrEMBL)
p38 MAPKGeneProductENSG00000185386 (Ensembl)
p53MetaboliteCHEBI:77731 (ChEBI)

Annotated Interactions

No annotated interactions

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