CytochromeP450 Epoxygenase Promotes Human Cancer Metastasis

Abstract

Cytochrome P450 (CYP) epoxygenases convert arachidonic acid to four regioisomeric epoxyeicosatrienoic acids (EET), which exert diverse biological activities in a variety of systems. We previously reported that the CYP2J2 epoxygenase is overexpressed in human cancer tissues and cancer cell lines and that EETs enhance tumor growth, increase carcinoma cell proliferation, and prevent apoptosis of cancer cells. Herein, we report that CYP epoxygenase overexpression or EET treatment promotes tumor metastasis independent of effects on tumor growth. In four different human cancer cell lines in vitro, overexpression of CYP2J2 or CYP102 F87V with an associated increase in EET production or addition of synthetic EETs significantly induced Transwell migration (4.5-to 5.5-fold), invasion of cells (3-to 3.5-fold), cell adhesion to fibronectin, and colony formation in soft agar. In contrast, the epoxygenase inhibitor 17-ODYA or infection with the antisense recombinant adeno-associated viral vector (rAAV)-CYP2J2 vector inhibited cell migration, invasion, and adhesion with an associated reduction in EET production. CYP overexpression also enhanced metastatic potential in vivo in that rAAV-CYP2J2-infected MDA-MB-231 human breast carcinoma cells showed 60% more lung metastases in athymic BALB/c mice and enhanced angiogenesis in and around primary tumors compared with control cells. Lung metastasis was abolished by infection with the antisense rAAV-CYP2J2 vector. CYP epoxygenase overexpression or EET treatment up-regulated the prometastatic matrix metalloproteinases and CD44 and down-regulated the antimetastatic genes CD82 and nm-23. Together, these data suggest that CYP epoxygenase inhibition may represent a novel approach to prevent metastasis of human cancers. [Cancer Res 2007;67(14):6665-74]

Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid

“…§, P < 0.05; § §, P < 0.01; § § §, P < 0.001 versus sEH / and solvent. (Jiang et al, 2007). For a while, sEH inhibitors looked like highly interesting compounds for the treatment of cardiovascular disorders (Imig and Hammock, 2009), but interest was dampened by speculation that the associated increase in EET levels could induce or promote cancer progression.…”

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

“…Aberrant CYP450 epoxygenase activity and EET synthesis was found to promote tumour metastasis, independent of tumour growth, in several human cancer cell lines [88]. In addition, it was shown to affect mitogen-activated protein kinase phosphatase-1 (MKP-1) mediated inactivation of c-Jun N-terminal kinase (JNK), which ultimately leads to the expression of cyclin D1 and cell proliferation [89].…”

CYP 2J2 and its metabolites (epoxyeicosatrienoic acids) attenuate cardiac hypertrophy by activating AMPK α2 and enhancing nuclear translocation of Akt1

“…The rAAV vectors (Serotype 9) containing CYP2J2 was produced by triple plasmid cotransfection in HEK293 cells as previously described (Jiang et al ., 2007). Purified rAAV9‐CYP2J2 (1 × 10 11 pfu) was injected into the caudal vein of AMPKα2 −/− and AMPKα2 +/+ mice 14 days prior to Ang II infusion.…”