New aspects of the role of hydroxyeicosatetraenoic acids in cell growth and cancer development

doi:10.1016/j.bcp.2008.07.033

Biochemical Pharmacology

Volume 77, Issue 1, 1 January 2009, Pages 1-10

https://doi.org/10.1016/j.bcp.2008.07.033 Get rights and content

Abstract

Lipoxygenase (LOX) pathway leads to the formation of leukotrienes and also catalyses the conversion of arachidonic acid (AA) to hydroperoxyeicosatetraenoic acids that are then reduced to hydroxyeicosatetraenoic acids (HETE) by glutathione peroxidase. There are four mammalian LOXs that produce 5-, 8-, 12- and 15-HETE, respectively. Cytochrome P-450 isozymes are also capable of metabolising AA to HETEs either by bis-allylic oxidation (lipoxygenase-like reaction) to generate 5-, 8-, 9-, 11-, 12- and 15-HETE; or by ϖ/ϖ-1 hydroxylation to yield 16-, 17-, 18-, 19- and 20-HETEs.

It is now widely recognised that HETEs have important physiological and pathological functions that modulate ion transport, renal and pulmonary functions, vascular tone and reactivity, and inflammatory and growth responses. They can be released during the action of growth factors and cytokines, reaching physiological concentrations higher than that of prostanoids and modulating the functions of these factors. Their effects can occur through receptor or non-receptor mechanisms. Recent reviews have summarised the effects of HETEs in vascular homeostasis or lung and renal physiology. The present review focuses on the emerging effects of HETEs on cell signalling and physiological cell growth. It also discusses current observations regarding the role of HETEs in apoptosis, angiogenesis, the proliferation of cancer cells and metastasis, which constitute a potential area for successful therapeutic intervention.

Section snippets

Enzymes involved in HETE generation

Polyunsaturated fatty acids, such as arachidonic acid (AA) are found esterified at the sn-2 position of membrane phospholipids. These fatty acids have been regarded as structural components of cell membranes whose main function is to regulate membrane permeability. However, AA is released following activation of phospholipase A₂s and subsequent metabolisation by cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P-450 (CYP) pathways [1], [2]. These enzymes insert oxygen at different

Effect of HETEs on cell signalling involved in cell growth

HETEs are involved in the cell signalling induced by several growth factors such as neurotensin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), serum, angiotensin II and insulin. As summarised in Table 1 these growth factors induce HETE synthesis by enhancing the expression/activity of LOXs or CYPs until they reach physiological concentrations higher than that of prostanoids [22], [23]. Consequently, LOX and CYP inhibitors modulate cell growth induced by numerous growth

Inhibition of apoptosis by HETEs

The induction of cell death is often preceded by an arrest in the cell cycle. Indeed there are substantial evidences that critical regulatory steps occur during the G₁ phase. As pointed out in the previous section, the impairment of HETE synthesis by LOX inhibitors induces cell arrest and apoptosis, whereas HETEs inhibit programmed cell death. Thus, LOX inhibitors induce apoptosis in vascular smooth muscle cells [77], W256 carcinosarcoma cells [78], prostate cancer cells [52], breast cancer

HETEs are involved in angiogenesis

Growth factors and hypoxia converge in the regulation of key angiogenic genes. The cellular expansion of tumours progressively distances cells from the vasculature, and thus from oxygen and nutrients. Consequently, tumour cells, like growing tissues or embryonic cells, emit signals that initiate the formation of new blood vessels. This adaptive process, termed angiogenesis, is a general feature of every tissue, mainly in the wound repair process, and is a prerequisite for tumour expansion

Regulation of adhesion, migration and invasion by HETEs

The ability of tumour to invade new tissues requires the complex interplay of various cell surface-associated elements that regulate the proteolytic disruption of the extracellular matrix (ECM) and the modification of cell adhesion properties. These cell–ECM interactions, necessary for metastasis, are mediated by integrins. Several studies have reported the role of HETEs, in particular 12-HETE, in the regulation of surface integrin expression. Thus, adhesion of B16 murine melanoma cell to

HETEs in normal and malignant tissue

The role of HETEs produced by LOX and CYP in the development and progression of cancer is complex due both to the variety of genes identified and the different profiles of LOX/CYP observed in tumour biopsies. 15-LOX-1 and 15-LOX-2 are usually preferentially expressed in normal tissue and benign lesions, whereas 5-LOX and 12-LOX are absent in normal epithelia, can be induced by pro-inflammatory stimuli, and are often expressed in epithelial cancers. Thus, 15-LOX-1 and 15-LOX-2 were found to be

Implications and future directions

This review aims to present a conceptual framework for integrative signalling and proposes HETEs as some of the mediators behind this process. The findings presented strengthen the hypothesis that not all lipid derived from AA are exclusively pro-inflammatory mediators. In addition, HETEs could be protective mediators involved in the resolution of inflammation and in promoting cell proliferation and wound healing though the activation of several mitogenic signal pathways. Indeed, there is

Acknowledgments

Original works described in this review were supported by Spanish Ministry of Education and Science (BFI2001-3397) (BFU2004-04960) and (BFU2007-61727). We thank Robin Rycroft for valuable assistance in the preparation of the manuscript.

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CommentaryNew aspects of the role of hydroxyeicosatetraenoic acids in cell growth and cancer development

Abstract

Section snippets

Enzymes involved in HETE generation

Effect of HETEs on cell signalling involved in cell growth

Inhibition of apoptosis by HETEs

HETEs are involved in angiogenesis

Regulation of adhesion, migration and invasion by HETEs

HETEs in normal and malignant tissue

Implications and future directions

Acknowledgments

FEBS Lett

Biochim Biophys Acta

J Biol Chem

Exp Eye Res

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

Kidney Int

J Biol Chem

J Biol Chem

J Lipid Res

Biochem Pharmacol

Exp Eye Res

Exp Eye Res

Exp Eye Res

Regul Pept

J Biol Chem

Trends Cardiovasc Med

J Biol Chem

Biochem Biophys Res Commun

Biochim Biophys Acta

J Biol. Chem

Biochem Pharmacol

Food Chem Toxicol

Prostaglandins Other Lipid Mediat

J Lipid Res

Prostaglandins

Atherosclerosis

Trends Cardiovasc Med

J Biol Chem

J Lipid Mediat Cell Signal

J Biol Chem

Biochem Pharmacol

Prostaglandins Leukot Essent Fatty Acids

Biochem Biophys Res Commun

Blood

Toxicol

Exp Cell Res

J Biol Chem

Prostaglandins, Leukotrienes Essent Fatty Acids

Prostaglandins, Leukotrienes Essent Fatty Acids

Cancer Lett

Food Chem Toxicol

Eicosanoid regulation of the renal vasculature

Am J Physiol Renal Physiol

Prostaglandins and leukotrienes: advances in eicosanoid biology

Science

Discovery of a second 15S-lipoxygenase in humans

Proc Natl Acad Sci USA

Biosynthesis of 12(S)-hydroxyeicosatetraenoic acid by bovine corneal epithelium

Acta Physiol Scand

P450 subfamily CYP2J and their role in the bioactivation of arachidonic acid in extrahepatic tissues

Drug Metab Rev

Human umbilical vein endothelial cells express P450 2C8 mRNA: cloning of endothelial P450 epoxygenase

Endothelium

Cytochromes P450 with bisallylic hydroxylation activity on arachidonic and linoleic acids studied with human recombinant enzymes and with human

J Pharmacol Exp Ther

Commentary
New aspects of the role of hydroxyeicosatetraenoic acids in cell growth and cancer development