20-HETE-producing enzymes are up-regulated in human cancers. Cancer Genomics Proteomics 2012;9(4):163-9
Date
07/17/2012Pubmed ID
22798501Pubmed Central ID
PMC3601443Scopus ID
2-s2.0-84864656181 (requires institutional sign-in at Scopus site) 54 CitationsAbstract
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.
Author List
Alexanian A, Miller B, Roman RJ, Sorokin AAuthor
Andrey Sorokin PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Cytochrome P-450 CYP4ACytochrome P-450 Enzyme System
Cytochrome P450 Family 4
Epithelial Cells
Gene Expression Regulation, Neoplastic
Humans
Hydroxyeicosatetraenoic Acids
Kidney Tubules, Proximal
Neoplasms
Tandem Mass Spectrometry
