Studies of Lipoxygenase Function

 
 
 
 

Studies of Lipoxygenase Function

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Title: Studies of Lipoxygenase Function
Author: McCabe, Noel Patrick
Description: Arachidonic acid metabolism leads to the production of biolipid mediatiors with important roles in multiple pathological processes including prostate cancer. Expression of platelet-type 12-lipoxygenase (P12-LOX) correlates with clinical stage and grade of prostate adenocarcinoma and overexpression in prostate cancer cells leads to large, highly vascularized tumors in a mouse model. The product of arachidonic acid metabolism via P12-LOX is 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), a lipid previously linked to angiogenesis. Although P12-LOX and its product, 12(S)-HETE, have been shown to play a role in prostate cancer biology, an underlying mechanism has yet to be characterized. Thus, PC-3 prostate cancer cells overexpressing P12-LOX were employed to define the function of 12(S)-HETE as an angiogenic factor. Overexpression of P12-LOX in prostate cancer cells resulted in increased 12(S)-HETE production and enhanced accumulation of the potent angiogenic protein vascular endothelial growth factor (VEGF). Elevated basal phosphorylation of the extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen activated protein kinase (MAPK) was found in cells overexpressing P12-LOX. Incubation of PC-3 and DU145 prostate cancer cells with 12(S)-HETE resulted in a significant increase in phosphorylated ERK1/2, whereas preincubation with pharmacological inhibitor/s of MEK and pertussis toxin (PTx) sensitive G-protein coupled receptors (GPCR) blocked 12(S)-HETE induced ERK1/2 phosphorylation. Additionally, inhibition of both MEK and PTx sensitive GPCRs reduced VEGF accumulation in culture media of cells overexpressing P12-LOX. These results indicate that P12-LOX overexpression by prostate cancer cells, a condition mirrored in prostate cancer patients, may have the untoward effect of increasing VEGF production and that this effect is due to the stimulation of ERK1/2 by 12(S)-HETE in a PTx sensitive GPCR mediated manner. Inhibition of P12-LOX in the treatment of prostate cancer is currently not a viable therapeutic strategy due to a lack of lipoxygenase inhibitor specificity. Using X-ray crystallographic analysis, the 3D interaction of curcumin with soybean lipoxygenase-3 was examined. These pilot studies may help in the development of novel, highly specific inhibitors of P12-LOX. Taken together, these data show that P12-LOX plays a significant role in prostate cancer induced angiogenesis by promoting VEGF production and that X-ray crystallography may prove beneficial in the development of specific inhibitors of P12-LOX.
Permanent Link: http://rave.ohiolink.edu/etdc/view?acc_num=mco1106061925
http://hdl.handle.net/2374.OX/18025
Date: 2005

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