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EET signaling in cancer

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Abstract

Inflammation and angiogenesis in the tumor microenvironment are increasingly implicated in tumorigenesis. Endogenously produced lipid autacoids, locally acting small-molecule mediators, play a central role in inflammation and tissue homeostasis. These lipid mediators, collectively referred to as eicosanoids, have recently been implicated in cancer. Although eicosanoids, including prostaglandins and leukotrienes, are best known as products of arachidonic acid metabolism by cyclooxygenases and lipoxygenases, arachidonic acid is also a substrate for another enzymatic pathway, the cytochrome P450 (CYP) system. This eicosanoid pathway consists of two main branches: ω-hydroxylases which converts arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases which converts it to four regioisomeric epoxyeicosatrienoic acids (EETs; 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET). EETs regulate inflammation and vascular tone. The bioactive EETs are produced predominantly in the endothelium and are mainly metabolized by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic acids. EET signaling was originally studied in conjunction with inflammatory and cardiovascular disease. Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology. To date, most research on eicosanoids in cancer has focused on the COX and LOX pathways. In contrast, the role of cytochrome P450-derived eicosanoids, such as EETs and HETEs, in cancer has received little attention. While CYP epoxygenases are expressed in human cancers and promote human cancer metastasis, the role of EETs (the direct products of CYP epoxygenases) in cancer remains poorly characterized. In this review, the emerging role of EET signaling in angiogenesis, inflammation, and cancer is discussed.

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Abbreviations

CYP and P450:

Cytochrome P450

COX:

Cyclooxygenase

LOX:

Lipoxygenase

EET:

Epoxyeicosatrienoic acid

HETE:

Hydroxyeicosatetraenoic acid

sEH:

Soluble epoxide hydrolase

DHET:

Dihydroxyeicosatrienoic acid

14,15-EEZE:

14,15-Epoxyeicosa-5(Z)-enoic acid

PGE2 :

Prostaglandin E2

LTB4 :

Leukotriene B4

VEGF:

Vascular endothelial growth factor

FGF-2:

Fibroblast growth factor-2

TGF-β:

Transforming growth factor beta

TNF-α:

Tumor necrosis factor-alpha

IL-1:

Interleukin-1

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

MAPK/ERK:

Mitogen-activated protein kinase/Extracellular signal-regulated kinase

ROS:

Reactive oxygen species

NF-κB:

Nuclear factor-kappaB

ICAM:

Intracellular adhesion molecule

VCAM-1:

Vascular cell adhesion molecule-1

HIF-1α:

Hypoxia-inducible factor-1α

NO:

Nitric oxide

eNOS:

Endothelial nitric oxide synthase

iNOS:

Inducible nitric oxide synthase

PI3K/Akt:

Phospatidylinositol-3-kinase/Akt

PPAR:

Peroxisome proliferator-activated receptor

RXR:

Retinoid X receptor

PPRE:

Peroxisome proliferator response element

PSA:

Prostate-specific antigen

MMP-9:

Metalloproteinase-9

CAM:

Chorioallantoic membrane

SK1:

Sphingosine kinase-1

AUDA-BE:

12-(3-Adamantan-1-yl-ureido)-dodecanoic acid butyl ester

NSAIDs:

Non-steroidal anti-inflammatory drugs

HB-EGF:

Heparin-binding epidermal growth factor-like growth factor

EPHX2:

Epoxide hydrolase 2

SCC:

Squamous cell carcinoma

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Acknowledgments

We thank Sui Huang and Arja Kaipainen for suggestions in preparing the manuscript; Kristin Johnson for preparation of figures. This work was supported by National Cancer Institute grant RO1CA148633-O1A1 (DP); 2PO1DK38226 (AP); Division of Intramural Research of the NIH, National Institute of Environmental Health Sciences - Z01 ES025034 and Z01 ES050167 (DCZ).

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Panigrahy, D., Greene, E.R., Pozzi, A. et al. EET signaling in cancer. Cancer Metastasis Rev 30, 525–540 (2011). https://doi.org/10.1007/s10555-011-9315-y

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