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20-HETE-producing enzymes are up-regulated in human cancers.

ABSTRACT: BACKGROUND:20-Hydroxyeicosatetraenoic acid (20-HETE), a metabolite of arachidonic acid (AA) produced by the CYP4A and CYP4F enzyme families has been reported to induce mitogenic and angiogenic responses both in vitro and in vivo, and inhibitors of this pathway reduced growth of brain and kidney tumors. MATERIALS AND METHODS:Real-Time PCR, western blot and immunohistochemistry were used to compare the expression of CYP4A/F mRNA and protein levels in human cancer tissue samples versus normal controls. Liquid chromatography/mass spectrometry analysis (LC-MS/MS) was performed to measure 20-HETE formation in tumor homogenates. Activation of Ras in human proximal tubule epithelial cells (HRPTEC) treated with stable agonist of 20-HETE was measured using a Ras pull-down detection kit. RESULTS:The expression of CYP4A/4F genes was markedly elevated in thyroid, breast, colon, and ovarian cancer samples in comparison to matched normal tissues. Furthermore, the levels of the CYP4F2 protein and of 20-HETE were higher in ovarian cancer samples compared to normal control tissues. A stable 20-HETE agonist induced activation of the small-GTPase Ras in HRPTEC cells. CONCLUSION:The present finding of elevated expression of CYP4A/F enzymes in human cancer tissue suggests that 20-HETE inhibitors and antagonists may be useful in the treatment of cancer.

SUBMITTER: Alexanian A

PROVIDER: S-EPMC3601443 | biostudies-literature | 2012 Jul-Aug

REPOSITORIES: biostudies-literature

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20-HETE-producing enzymes are up-regulated in human cancers.

Alexanian Anna A Miller Bradley B Roman Richard J RJ Sorokin Andrey A

Cancer genomics & proteomics 20120701 4

<h4>Background</h4>20-Hydroxyeicosatetraenoic acid (20-HETE), a metabolite of arachidonic acid (AA) produced by the CYP4A and CYP4F enzyme families has been reported to induce mitogenic and angiogenic responses both in vitro and in vivo, and inhibitors of this pathway reduced growth of brain and kidney tumors.<h4>Materials and methods</h4>Real-Time PCR, western blot and immunohistochemistry were used to compare the expression of CYP4A/F mRNA and protein levels in human cancer tissue samples vers ...[more]

PMID: 22798501

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Project description:20-HETE is a potent vasoconstrictor that is implicated in the regulation of blood pressure, cerebral blood flow and neuronal death following ischemia. Numerous human genetic studies have shown that inactivating variants in the cytochrome P450 enzymes that produce 20-HETE are associated with hypertension, stroke and cerebrovascular disease. However, little is known about the expression and cellular distribution of the cytochrome P450A enzymes (CYP4A) that produce 20-HETE or the newly discovered 20-HETE receptor (GPR75) in the brain. The present study examined the cell types and regions in the rat forebrain that express CYP4A and GPR75. Brain tissue slices from Sprague Dawley (SD), Dahl Salt-Sensitive (SS) and CYP4A1 transgenic rat strains, as well as cultured human cerebral pericytes and cerebral vascular smooth muscle cells, were analyzed by fluorescent immunostaining. Tissue homogenates from these strains and cultured cells were examined by Western blot. In the cerebral vasculature, CYP4A and GPR75 were expressed in endothelial cells, vascular smooth muscle cells and the glial limiting membrane of pial arteries and penetrating arterioles but not in the endothelium of capillaries. CYP4A, but not GPR75, was expressed in astrocytes. CYP4A and GPR75 were both expressed in a subpopulation of pericytes on capillaries. The diameters of capillaries were significantly decreased at the sites of first and second-order pericytes that expressed CYP4A. Capillary diameters were unaffected at the sites of other pericytes that did not express CYP4A. These findings implicate 20-HETE as a paracrine mediator in various components of the neurovascular unit and are consistent with 20-HETE's emerging role in the regulation of cerebral blood flow, blood-brain barrier integrity, the pathogenesis of stroke and the vascular contributions to cognitive impairment and dementia. Moreover, this study highlights GPR75 as a potential therapeutic target for the treatment of these devastating conditions.

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20-HETE-producing enzymes are up-regulated in human cancers.

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20-HETE-producing enzymes are up-regulated in human cancers.

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