The Anti-tumorigenic Properties of Peroxisomal Proliferator-activated Receptor α Are Arachidonic Acid Epoxygenase-mediated

Ambra Pozzi,Vlad Popescu,Shilin Yang,Shaojun Mei,Mingjian Shi,Satu M Puolitaival,Richard M Caprioli,Jorge H Capdevila

doi:10.1074/jbc.m109.081554

Abstract

Prevalence and mortality make cancer a health challenge in need of effective and better tolerated therapeutic approaches, with tumor angiogenesis identified as a promising target for drug development. The epoxygenase products, the epoxyeicosatrienoic acids, are pro-angiogenic, and down-regulation of their biosynthesis by peroxisomal proliferator-activated receptor alpha (PPARalpha) ligands reduces tumor angiogenesis and growth. Endothelial cells lacking a Cyp2c44 epoxygenase, a PPARalpha target, show reduced proliferative and tubulogenic activities that are reversed by the enzyme's metabolites. In a mouse xenograft model of tumorigenesis, disruption of the host Cyp2c44 gene causes marked reductions in tumor volume, mass, and vascularization. The relevance of these studies to human cancer is indicated by the demonstration that: (a) activation of human PPARalpha down-regulates endothelial cell CYP2C9 epoxygenase expression and blunts proliferation and tubulogenesis, (b) in a PPARalpha-humanized mouse model, activation of the receptor inhibits tumor angiogenesis and growth, and (c) the CYP2C9 epoxygenase is expressed in the vasculature of human tumors. The identification of anti-angiogenic/anti-tumorigenic properties of PPARalpha points to a role for the receptor and its epoxygenase regulatory target in the pathophysiology of cancer, and for its ligands as candidates for the development of a new generation of safer and better tolerated anti-cancer drugs.

Highlights

Despite advances in diagnosis and treatment, cancer continues to pose major clinical challenges and is the focus of efforts to develop therapies that combine effectiveness with low toxicity
The demonstration that the anti-tumorigenic effects of PPAR␣ ligand activation were associated with reductions in the endothelial expression of the murine Cyp2c44 epoxygenase and in the levels of plasma and endothelial epoxyeicosatrienoic acids (EETs) [6], suggested pro-angiogenic and pro-tumorigenic roles for this epoxygenase, and pointed to this enzyme as a target of the anti-tumorigenic effects resulting from PPAR␣ activation [6]
To characterize the origin of the pro-angiogenic EETs, and the organ target of the anti-tumorigenic responses resulting from PPAR␣ activation, we compared the effects of Wyeth 14,643 (Wyeth) [6], a PPAR␣-selective ligand [17, 18, 34], in the levels of EETs present in the plasma of WT and KO mice

Summary

Introduction

Despite advances in diagnosis and treatment, cancer continues to pose major clinical challenges and is the focus of efforts to develop therapies that combine effectiveness with low toxicity. The down- and up-regulation of VEGF and thrombospondin, respectively [7], or reductions in the expression of the murine Cyp2c44 epoxygenase and biosynthesis of pro-angiogenic EETs [6] were proposed as the mechanisms responsible for the anti-tumorigenic effects of PPAR␣ ligands.

Results

Conclusion