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Cytochrome P450 Epoxygenases and Cancer: a Genetic and a Molecular Perspective

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Cytochrome P450 Epoxygenases and Cancer: a Genetic and a Molecular Perspective Pharmacology & Therapeutics 196 (2019) 183–194 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Cytochrome P450 epoxygenases and cancer: A genetic and a molecular perspective Lindsay N. Sausville a, Scott M. Williams a, Ambra Pozzi b,c,⁎ a Department of Population and Quantitative Health Science, Case Western Reserve University, Cleveland, OH, United States b Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States c Department of Veterans Affairs, Nashville, TN, United States article info abstract Keywords: Cytochrome CYP450 epoxygenases catalyze the epoxidation of polyunsaturated fatty acids including arachidonic Angiogenesis acid, eicosapentaenoic acid, and docosahexaenoic acid. The arachidonic acid-derived products are potent pro- Cancer angiogenic lipids and promote tumor development and growth. On the other hand, eicosapentaenoic acid- and Growth factors Single nucleotide polymorphism docosahexaenoic acid-derived products inhibit angiogenesis and play a protective role in certain pathological Lipids conditions including cancer. Increased expression of CYP2C epoxygenases, together with increased levels of Endothelial cells their arachidonic acid-derived products, is often observed in tumors and tumor-associated vasculature, making these enzymes an ideal target for anti-cancer therapies. Yet, given the pro- and anti-angiogenic action of these enzymes, a better understanding of the specific roles of their products in the regulation of endothelial cell func- tion and cancer development is required. In this review, we provide an overview of the role of CYP450 epoxygenase-derived lipids, with emphasis on arachidonic acid-derived products, in the regulation of endothelial cell function both in physiological and pathological conditions. Moreover, we discuss the impact of genetic poly- morphisms in CYP450 epoxygenases on cancer risk, and we discuss advantages and limitation of approaches to target these enzymes and their products in pathological angiogenesis and cancer. © 2018 Elsevier Inc. All rights reserved. Contents 1. Introduction............................................... 184 2. CYP450epoxygenase-derivedEETs.................................... 184 3. NonAA-derivedCYP450epoxygenasesproducts.............................. 187 4. TargetingCYP450epoxygenasesandtheirproducts............................. 188 5. CYP450epoxygenasesinhumantumors.................................. 190 6. Conclusion............................................... 191 Conflictofintereststatement......................................... 192 Acknowledgments.............................................. 192 References.................................................. 192 Abbreviations: AA, arachidonic acid; AKT, protein kinase B; CI, confidence interval; COX, cyclooxygenase; CRC, colorectal cancer; CYP450, cytochrome P450; EC, endothelial cell; EDP, epoxydocosapentaenoic acid; EEQ, epoxyeicosatetraenoic acid; EET, epoxyeicosatrienoic acid; ERK, extracellular signal–regulated kinase; FGF, fibroblast growth factor; GPR, G protein- coupled receptor; LOX, lipoxygenase; NSAIDs, nonsteroidal anti-inflammatory drugs; NSCLC, non-small cell lung cancer; PPAR, peroxisome proliferator-activated receptor; PTUPB, (4- (5-phenyl-3-{3-[3-(4-trifluoromethyl-phenyl)-ureido]-propyl}-pyrazol-1-yl)-benzenesulfonamide; PUFA, polyunsaturated fatty acid; sEH, soluble epoxide hydrolase; SNP, single nucle- otide polymorphism; VEGF, vascular endothelial growth factor; WT, wild-type. ⁎ Corresponding author at: Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University School of Medicine, Medical Center North, B3115 Nashville, TN, USA. E-mail address: [email protected] (A. Pozzi). https://doi.org/10.1016/j.pharmthera.2018.11.009 0163-7258/© 2018 Elsevier Inc. All rights reserved. 184 L.N. Sausville et al. / Pharmacology & Therapeutics 196 (2019) 183–194 1. Introduction Campbell & Falck, 2007; Chacos et al., 1983; Yu et al., 2000; Zeldin et al., 1993)(Fig. 1). 1.1. Overview of arachidonic acid metabolism pathway In addition to AA, CYP450 epoxygenases catalyze the epoxidation of other lipids and xenobiotic substrates (Fer et al., 2008; Oliw, 1994; Eicosanoids represent a class of lipid signaling molecules with prom- Spector & Kim, 2015; Van Booven et al., 2010). Metabolism of the ω-3 inent roles in inflammation, cancer, and angiogenesis (Capdevila & polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and Falck, 2001; Schneider & Pozzi, 2011). Various eicosanoids can be gener- docosahexaenoic acid (DHA) by CYP450 epoxygenases generates ated from arachidonic acid (AA) through the cyclooxygenase (COX), epoxyeicosatetraenoic acid (EEQ) and epoxydocosapentaenoic lipoxygenase (LOX), and cytochrome P450 monooxygenase (CYP450) acid (EDP) regioisomers, respectively (Fer et al., 2008; Westphal, pathways. Each pathway uses unique enzymes to synthesize specificei- Konkel, & Schunck, 2011)(Fig. 2). EEQs and EDPs can be subsequently cosanoids, and each eicosanoid elicits distinct biological effects. In can- hydrolyzed by sEH to dihydroxyeicosatetraenoic acids and cer, these biological effects may be exerted on tumor or dihydroxydocosapentaenoic acids, respectively (Arnold et al., 2010) microenvironment cells (Hanahan & Weinberg, 2011; Schneider & (Fig. 2). Finally, as phase I detoxification enzymes, the CYP450 Pozzi, 2011). The effects of COX- and LOX-derived eicosanoids have epoxygenases oxidize a number of xenobiotics including amiodarone, been relatively well studied in cancer, especially those of tumor- cyclosporine, non-steroidal anti-inflammatory drugs (NSAIDs), pacli- promoting prostaglandin E2. While most eicosanoids synthesized by taxel, tamoxifen, and warfarin (Kerb et al., 2009;C.A.Lee et al., 2010; the COX and LOX pathways promote tumorigenesis, exceptions exist, C. R. Lee, Goldstein, & Pieper, 2002; Rahman, Korzekwa, Grogan, such as prostaglandin I2 (Schneider & Pozzi, 2011). In addition to the Gonzalez, & Harris, 1994). In this review, we focus on the putative role COX- and LOX-derived eicosanoids, metabolites derived from CYP450 of EETs as pro-angiogenic and pro-tumorigenic lipids, their mechanism monooxygenases also regulate cancer development and growth and of action, and approaches to target these lipids in pathological they can exert both pro- and anti-tumorigenic effects. conditions. The AA CYP450 monooxygenases consist of epoxygenases (CYP2 iso- forms) and ω-hydroxylases (CYP4 isoforms) (Schneider & Pozzi, 2011) 2. CYP450 epoxygenase-derived EETs (Fig. 1). CYP450 ω-hydroxylases oxidize AA to 19- or 20- hydroxyeicosatetraenoic acids. Epoxidation of AA by the CYP450 Synthesis of EETs represents one mechanism by which CYP450 epoxygenases produces four epoxyeicosatrienoic acid (EET) epoxygenases influence a diverse number of biological processes. regioisomers: 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET (Zeldin, CYP2C8, CYP2C9, CYP2J2, and CYP3A4 are the major enzymes responsi- 2001)(Fig. 1). Subsequent metabolism by the soluble epoxide hydro- ble for the conversion of AA to EETs in humans, while Cyp2c44, the lase (sEH) converts EETs into corresponding dihydroxyeicosatrienoic functional homolog of CYP2C9, is one of the major CYP450 epoxygenase acids, lipids with less potent biological effects (Campbell et al., 2002; in mice (Daikh, Lasker, Raucy, & Koop, 1994; Pozzi et al., 2005, 2010; Rifkind, Lee, Chang, & Waxman, 1995;S.Wu, Moomaw, Tomer, Falck, Fig. 1. Metabolism of arachidonic acid (AA) by the cytochrome P450 monooxygenases. AA is metabolized by P450 ω-hydroxylases (CYP4) to 19- or 20-hydroxyeicosatetraenoic acid (HETE). In addition, AA is metabolized by P450 epoxygenases (CYP2C, 2J, and 3A) to 5,6-, 8,9-, 11,12- or 14,15-epoxyeicosatranoic acid (EET). Subsequent metabolism by the soluble epoxide hydrolase (sEH) converts EETs into corresponding dihydroxyeicosatrienoic acids (DHET). L.N. Sausville et al. / Pharmacology & Therapeutics 196 (2019) 183–194 185 COOH COOH EPA DHA CYP epoxygenases CYP epoxygenases 4,5-EDP 5,6-EEQ 7,8-EDP 8,9-EEQ 10,11-EDP 11,12-EEQ 13,14-EDP 14,15-EEQ 16,17-EDP COOH 17,18-EEQ 19,20-EDP COOH O O sEH sEH 4,5-DHDP 5,6-DHEQ 7,8-DHDP 8,9-DHEQ 10,11-DHDP COOH 11,12-DHEQ 13,14-DHDP 14,15-DHEQ 16,17-DHDP COOH HO OH 17,18-DHEQ 19,20-DHDP HO OH Fig. 2. Metabolism of ω-3 polyunsaturated fatty acids by CYP450 epoxygenases. Metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by CYP450 epoxygenases generates 5 epoxyeicosatetraenoic acids (EEQ, 17,18-EEQ shown) and 6 epoxydocosapentaenoic acids (EDP, 19,20-EDP shown). EEQs and EDPs can be subsequently hydrolyzed by soluble hepoxihydrolase (sEH) to 5 dihydroxyeicosatetraenoic acids (DHEQ, 17,18-DHEQ shown) and 6 dihydroxydocosapentaenoic acids (DHDP, 13,14-DHDP shown). & Zeldin, 1996; Zeldin, Dubois, Falck, & Capdevila, 1995). CYP450 0–5 μM range enhance pulmonary EC proliferation with maximum ef- epoxygenases exhibit regioselectivity in that a given epoxygenase is fect observed at 1 μM, but 5,6-EET induced the most proliferation more efficient at producing a particular EET regioisomer(s) (Daikh, (Pozzi et al., 2005). In line with this finding, EET regioisomers propagate Lasker, Raucy, & Koop, 1994; Rifkind, Lee, Chang, & Waxman, 1995;S. their mitogenic effects through different signaling cascades, with pro- Wu, Moomaw, Tomer, Falck, & Zeldin, 1996; Zeldin, Dubois, Falck, & tein kinase B (AKT) mediating the effects
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