Cytochrome P450-CYP2 Family-Epoxygenase Role in Inflammation and Cancer

Chen, Chen; Wang, Dao Wen

doi:10.1016/bs.apha.2015.04.005

Cited by 17 publications

(8 citation statements)

References 114 publications

(125 reference statements)

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“…Finally, the cytochrome P450 pathway results in the production of epoxyeicosatrienoic acids and the hydroxyeicosastetraeinoic (Chen and Wang, 2015). These molecules have been shown to have vasculo-protective effects through mediating vasodilation and angiogenesis (Evangelista et al, 2020).…”

Section: Pathways Of Eicosanoid Productionmentioning

confidence: 99%

Eicosanoids in Cancer: New Roles in Immunoregulation

2020

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Eicosanoids represent a family of active biolipids derived from arachidonic acid primarily through the action of cytosolic phospholipase A2-α. Three major downstream pathways have been defined: the cyclooxygenase (COX) pathway which produces prostaglandins and thromboxanes; the 5-lipoxygenase pathway (5-LO), which produces leukotrienes, lipoxins and hydroxyeicosatetraenoic acids, and the cytochrome P450 pathway which produces epoxygenated fatty acids. In general, these lipid mediators are released and act in an autocrine or paracrine fashion through binding to cell surface receptors. The pattern of eicosanoid production is cell specific, and is determined by cell-specific expression of downstream synthases. Increased eicosanoid production is associated with inflammation and a panel of specific inhibitors have been developed designated non-steroidal anti-inflammatory drugs. In cancer, eicosanoids are produced both by tumor cells as well as cells of the tumor microenvironment. Earlier studies demonstrated that prostaglandin E2, produced through the action of COX-2, promoted cancer cell proliferation and metastasis in multiple cancers. This resulted in the development of COX-2 inhibitors as potential therapeutic agents. However, cardiac toxicities associated with these agents limited their use as therapeutic agents. The advent of immunotherapy, especially the use of immune checkpoint inhibitors has revolutionized cancer treatment in multiple malignancies. However, the majority of patients do not respond to these agents as monotherapy, leading to intense investigation of other pathways mediating immunosuppression in order to develop rational combination therapies. Recent data have indicated that PGE2 has immunosuppressive activity, leading to renewed interest in targeting this pathway. However, little is known regarding the role of other eicosanoids in modulating the tumor microenvironment, and regulating anti-tumor immunity. This article reviews the role of eicosanoids in cancer, with a focus on their role in modulating the tumor microenvironment. While the role of PGE2 will be discussed, data implicating other eicosanoids, especially products produced through the lipoxygenase and cytochrome P450 pathway will be examined. The existence of small molecular inhibitors and activators of eicosanoid pathways such as specific receptor blockers make them attractive candidates for therapeutic trials, especially in combination with novel immunotherapies such as immune checkpoint inhibitors.

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Section: Pathways Of Eicosanoid Productionmentioning

confidence: 99%

Eicosanoids in Cancer: New Roles in Immunoregulation

2020

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“…CYP2C8 participates in the metabolism of arachidonic acid to biologically active epoxyeicosatrienoic acids (e.g., 11-, 13-, or 15-hydroxyeicosatrienoic acid), involved in the regulation of numerous physiologic processes, e.g., vascular function, blood pressure regulation, pancreatic peptide hormone secretion, and platelet aggregation (Daikh et al, 1994;Rifkind et al, 1995;Zeldin et al, 1995). The roles of CYP2C8 and other CYP enzymes in inflammation, cardiovascular disease, and cancer were recently reviewed by Chen and Wang (2015) and Fleming (2014).…”

Section: B Endogenous and Natural Compoundsmentioning

confidence: 99%

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

et al. 2015

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“…Mono‐hydroxylated derivatives of AA, LA, DGLA, and other PUFAs can be formed from their precursor fatty acids via enzymatic and/or non‐enzymatic catalysed reactions (supplementary material, Figure S1). In light of this complexity, we investigated lipid mediator relationships within normal and neoplastic (hyperplastic and cancerous) endometrium (Figure D–F).…”

Section: Resultsmentioning

confidence: 99%

“…the anti‐inflammatory PGE 1 and PGE 3 ) from dihomo‐γ‐linolenic acid (DGLA) and eicosapentaenoic acid (EPA), respectively. AA and other PUFAs are also oxygenated by lipoxygenase (LOX) and cytochrome P450 (CYP450) enzymes to form various bioactive lipids, including hydroxyeicosatetraenoic acids (HETEs), hydroxyoctadecadienoic acids (HODEs), leukotrienes, lipoxins, and epoxyeicosatrienoic acids (EETs) . While many of these have been implicated in carcinogenesis in in vitro or murine models, studies on clinical specimens have largely relied on inference from expression of associated metabolic genes, or ELISA‐based eicosanoid measurements, which often lack specificity .…”

Section: Introductionmentioning

confidence: 99%

Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5‐lipoxygenase expression in aggressive subtypes of endometrial cancer

Cummings

Massey

Mappa

et al. 2018

The Journal of Pathology

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Eicosanoids comprise a diverse group of bioactive lipids which orchestrate inflammation, immunity, and tissue homeostasis, and whose dysregulation has been implicated in carcinogenesis. Among the various eicosanoid metabolic pathways, studies of their role in endometrial cancer (EC) have very much been confined to the COX-2 pathway. This study aimed to determine changes in epithelial eicosanoid metabolic gene expression in endometrial carcinogenesis; to integrate these with eicosanoid profiles in matched clinical specimens; and, finally, to investigate the prognostic value of candidate eicosanoid metabolic enzymes. Eicosanoids and related mediators were profiled using liquid chromatography-tandem mass spectrometry in fresh frozen normal, hyperplastic, and cancerous (types I and II) endometrial specimens (n = 192). Sample-matched epithelia were isolated by laser capture microdissection and whole genome expression analysis was performed using microarrays. Integration of eicosanoid and gene expression data showed that the accepted paradigm of increased COX-2-mediated prostaglandin production does not apply in EC carcinogenesis. Instead, there was evidence for decreased PGE /PGF inactivation via 15-hydroxyprostaglandin dehydrogenase (HPGD) in type II ECs. Increased expression of 5-lipoxygenase (ALOX5) mRNA was also identified in type II ECs, together with proportional increases in its product, 5-hydroxyeicosatetraenoic acid (5-HETE). Decreased HPGD and elevated ALOX5 mRNA expression were associated with adverse outcome, which was confirmed by immunohistochemical tissue microarray analysis of an independent series of EC specimens (n = 419). While neither COX-1 nor COX-2 protein expression had prognostic value, low HPGD combined with high ALOX5 expression was associated with the worst overall and progression-free survival. These findings highlight HPGD and ALOX5 as potential therapeutic targets in aggressive EC subtypes. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Cytochrome P450-CYP2 Family-Epoxygenase Role in Inflammation and Cancer

Cited by 17 publications

References 114 publications

Eicosanoids in Cancer: New Roles in Immunoregulation

Eicosanoids in Cancer: New Roles in Immunoregulation

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5‐lipoxygenase expression in aggressive subtypes of endometrial cancer

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