Cytochrome P450 2J2 Promotes the Neoplastic Phenotype of Carcinoma Cells and Is Up-regulated in Human Tumors

Abstract

Cytochrome P450 (CYP) arachidonic acid epoxygenase 2J2 converts arachidonic acid to four regioisomeric epoxyeicosatrienoic acids, which exert diverse biological activities in cardiovascular system and endothelial cells. However, it is unknown whether this enzyme highly expresses and plays any role in cancer. In this study, we found that very strong and selective CYP2J2 expression was detected in human carcinoma tissues in 101 of 130 patients (77%) as well as eight human carcinoma cell lines but undetectable in adjacent normal tissues and nontumoric human cell lines by Western, reverse transcription-PCR, and immunohistochemical staining. In addition, forced overexpression of CYP2J2, and CYP BM3F87V or addition of epoxyeicosatrienoic acids (EET) in cultured carcinoma cell lines in vitro markedly accelerated proliferation by analyses of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, cell accounts, and cell cycle analysis, and protected carcinoma cells from apoptosis induced by tumor necrosis factor A (TNF-A) in cultures. In contrast, antisense 2J2 transfection or addition of epoxygenase inhibitors 17-ODYA inhibited proliferation and accelerated cell apoptosis induced by TNF-A. Examination of signaling pathways on the effects of CYP2J2 and EETs revealed activation of mitogenactivated protein kinases and PI3 kinase-AKT systems and elevation of epithelial growth factor receptor phosphorylation level. These results strongly suggest that CYP epoxygenase 2J2 plays a previously unknown role in promotion of the neoplastic cellular phenotype and in the pathogenesis of a variety of human cancers. (Cancer Res 2005; 65(11): 4707-15)

Antiangiogenic Effect of Inhibitors of Cytochrome P450 on Rats with Glioblastoma Multiforme

“…In the current study, both 17-ODYA and miconazole were equally effective in reducing the overall tumor volume. However, the effect of 17-ODYA was more In the present study, we also found that expression of the CYP2C11 epoxygenase protein is markedly upregulated in tumor tissue compared with the normal tissue, which is consistent with a previous finding that CYP2J2 epoxygenase promotes the neoplastic phenotype of carcinoma cells and is upregulated in human tumors (Jiang et al, 2005). However, in our studies 17-ODYA and miconazole have no effect on EET and DHET (dihydroxy …”

“…The dosage used is justified when taking into consideration the average volume of the tumor, which is typically around 50 mm 3 and the rate of delivery of the drug by the osmotic minipump at 0.5 mL /h. Furthermore, in recent studies Jiang et al (2005) have reported the inhibition of proliferation of a number of carcinoma cell types (Tca-8113, A549, HepG2, and Ncl-H446) by 17-ODYA at concentrations of 0.05 to 0.1 mmol/L. In the current study, both 17-ODYA and miconazole were equally effective in reducing the overall tumor volume.…”

Selective, competitive and mechanism-based inhibitors of human cytochrome P450 2J2

“…This set of compounds should be very useful to determine the biological role of each P450 in the cardiovascular system. Finally, given the recent findings suggesting that CYP2J2 may represent a potential target for therapy of human cancers [23], studies are currently underway to test the above described CYP2J2 inhibitors as potential therapeutic agents for cancer.…”

“…EETs and EETs-derived metabolites are also involved in a host of processes related to cancer cell behavior, angiogenesis and tumor pathogenesis [21,22]. Very recent data suggest that CYP2J2 promotes the neoplastic phenotype of carcinoma cells and may represent a novel biomarker and potential target for therapy of human cancers [23]. Besides these possible roles in the metabolism of endogenous compounds, CYP2J2 could be implied in the metabolism of some drugs, especially at the intestinal level.…”

Interaction of brain fatty acid-binding protein with the polyunsaturated fatty acid environment as a potential determinant of poor prognosis in malignant glioma

“…Recent studies indicate that some CYP-mediated metabolites of AA possess protumorigenic, pro-angiogenic, pro-migratory and pro-invasive properties in different cancer types [106][107][108][109]. For example, the CYP epoxygenase 2J2 transforms AA into four regioisomeric epoxyeicosatrienoic acids (EETs).…”