title: Hepoxilin A(3) protects β-cells from apoptosis in contrast to its precursor, 12-hydroperoxyeicosatetraenoic acid.
abstract: Pancreatic β-cells have a deficit of scavenging enzymes such as catalase (Cat) and glutathione peroxidase (GPx) and therefore are susceptible to oxidative stress and apoptosis. Our previous work showed that, in the absence of cytosolic GPx in insulinoma RINm5F cells, an intrinsic activity of 12 lipoxygenase (12(S)-LOX) converts 12S-hydroperoxyeicosatetraenoic acid (12(S)-HpETE) to the bioactive epoxide hepoxilin A(3) (HXA(3)). The aim of the present study was to investigate the effect of HXA(3) on apoptosis as compared to its precursor 12(S)-HpETE and shed light upon the underlying pathways. In contrast to 12(S)-HpETE, which induced apoptosis via the extrinsic pathway, we found HXA(3) not only to prevent it but also to promote cell proliferation. In particular, HXA(3) suppressed the pro-apoptotic BAX and upregulated the anti-apoptotic Bcl-2. Moreover, HXA(3) induced the anti-apoptotic 12(S)-LOX by recruiting heat shock protein 90 (HSP90), another anti-apoptotic protein. Finally, a co-chaperone protein of HSP90, protein phosphatase 5 (PP5), was upregulated by HXA(3), which counteracted oxidative stress-induced apoptosis by dephosphorylating and thus inactivating apoptosis signal-regulating kinase 1 (ASK1). Taken together, these findings suggest that HXA(3) protects insulinoma cells from oxidative stress and, via multiple signaling pathways, prevents them from undergoing apoptosis.
authors.affiliation: Department of Gynecology, Eicosanoid and Lipid Research Division and Centre for Experimental Gynecology and Breast Research, Charite-Campus Benjamin Franklin, Berlin, Germany. patapia.zafeiriou@med.uni-goettingen.de
authors.forename: Maria-Patapia
authors.initials: MP
authors.lastname: Zafiriou
authors.forename: Laura Cecilia
authors.initials: LC
authors.lastname: Zelarayan
authors.forename: Claudia
authors.initials: C
authors.lastname: Noack
authors.forename: Anke
authors.initials: A
authors.lastname: Renger
authors.forename: Santosh
authors.initials: S
authors.lastname: Nigam
authors.forename: Athanassia
authors.initials: A
authors.lastname: Siafaka-Kapadai
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000494:pharmacology*; D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015151:Immunoblotting; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C038243:8-hydroxy-11,12-epoxyeicosa-5,9,14-trienoic acid; D001092:Arachidonate 12-Lipoxygenase; D048848:MAP Kinase Kinase Kinase 5; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5; D053148:Caspase 3; D015126:8,11,14-Eicosatrienoic Acid