Platelet-type 12-lipoxygenase activates NF-kappaB in prostate cancer cells.
Platelet-type arachidonate 12-lipoxygenase (12-LOX) is highly expressed in many types of cancers and plays an important role in cancer pathophysiology. Arachidonic acid metabolism by 12-LOX results in the stable end product 12(S)-hydroxy eicosatetraenoic acid (12(S)-HETE), which is a signaling molecule with effects on cell proliferation, motility, invasiveness, angiogenesis, and inhibition of apoptosis. The myriad biological activities manifested by 12(S)-HETE appear to be mediated, at least in part, by the activation of NF-kappaB. Overexpression of the 12-LOX in PC-3 prostate cancer cells resulted in the constitutive activation of the transcription factor. The enzymatic product of arachidonic acid metabolism, 12(S)-HETE, mediates the activation of NF-kappaB by the 12-LOX. 12(S)-HETE treatment of PC-3 cells induced the degradation of IkappaB by the S6 proteasomal pathway and the activated NF-kappaB translocated to the nucleus causing kappaB-induced transcription. Specificity of the NF-kappaB activation by 12(S)-HETE was established by the use of a 12-LOX-specific inhibitor and 13(S)-HODE, a known 12(S)-HETE antagonist. Considering the known involvement of MAP kinase pathway in NF-kappaB activation and that of 12(S)-HETE in MAP kinase pathway, 12-LOX present in prostate cancer tissues may contribute to the constitutive activation of NF-kappaB in prostate cancer cells.
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001092:Arachidonate 12-Lipoxygenase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016718:Arachidonic Acid / Q000378:metabolism; D001792:Blood Platelets / Q000201:enzymology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000378:metabolism; D007976:Leupeptins / Q000494:pharmacology; D008041:Linoleic Acids / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D020672:I-kappa B Proteins; D007976:Leupeptins; D008041:Linoleic Acids; D016859:Lipoxygenase Inhibitors; D016328:NF-kappa B; D014157:Transcription Factors; D016718:Arachidonic Acid; C024348:13-hydroxy-9,11-octadecadienoic acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001092:Arachidonate 12-Lipoxygenase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde