Involvement of 5-lipoxygenase in survival of Epstein–Barr virus (EBV)-converted B lymphoma cells Maria Cristina Belfiore a , Alessandro Natoni a , Roberta Barzellotti a , Nicolo’ Merendino b , Gloria Pessina b , Lina Ghibelli c , Giampiero Gualandi a, * a DABAC, Universita’ della Tuscia,Via SC de Lellis, 01100 Viterbo, Italy b DiSA Universita’ della Tuscia,Via SC de Lellis, 01100 Viterbo, Italy c Dipartimento di Biologia, Universita’ Tor Vergata, Roma Received 15 June 2006; received in revised form 14 February 2007; accepted 12 March 2007 Abstract Epstein–Barr Virus (EBV) is involved in the progression of lymphomas through still unknown mechanism involving increased resistance to induced apoptosis. We show here that in a set of apoptosis-resistant EBV-converted Burkitt’s lym- phoma clones, 5- and 12-lipoxygenases (LOXs) are over-expressed. Further investigations on 5-LOX showed that resis- tance to apoptosis increases parallely with the expression of 5-lipoxygenase (5-LOX). Inhibitors of 5-LOX: (a) decrease peroxides level, indicating that this enzyme promotes the generation of oxidative stress in EBV+ cells, and (b) potently induce apoptosis in the EBV resistant cell line E2R. 5- and 15-HETE, the products of the 5 and 15-LOXs, respectively, counteract 5-LOX inhibitor induced apoptosis, indicating that products of arachidonate metabolism, rather than perox- ides, trigger a signal transduction that is required for survival of the EBV-converted cells. These findings suggest that 5- and, to a lesser extent, other LOXs, that are involved in tumor progression of several cell types, may also participate in lymphomagenesis, especially that EBV-mediated. Ó 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Apoptosis; Peroxides; LOXs; Epstein–Barr virus; Lymphoma cells; Quantitative RT-PCR 1. Introduction Many factors are involved in putative EBV tumorigenesis, among them important are de-regu- lation of cell cycle, increase in survival signals and augmented apoptosis resistance [1–3]. Multiple routes seem to be involved in EBV-mediated resis- tance to apoptosis, such as the expression of latent membrane proteins LMP-1 and LMP-2A which activate the PI3K/Akt [4,5] or NF-jB [6] survival/ 0304-3835/$ - see front matter Ó 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2007.03.010 Abbreviations: LOX, lipoxygenase; FLAP, 5-lipoxygenase acti- vating protein; EBV, Epstein–Barr virus ; LMP1, latent mem- brane protein 1; COX, cyclo-oxygenase; NF-jB, nuclear factor kB; HETE, hydroxyeicosatetraenoic acid; 13-S-HODE, 13-S-h- ydroxyoctadecadienoic acid; BL, Burkitt’s lymphoma; IAP, inh- ibitor of apoptosis protein; ROS, reactive oxygen species; NDGA, nordihydroguaiaretic acid; CAPE, Caffeic acid phenyl ether; DCFH-DA, 2’,7 0 -dichloroflurorescein diacetate; NOS, nitric oxide synthase. * Corresponding author. Tel.: +39 0761 357315; fax: +39 0761 357242. E-mail address: gualandi@unitus.it (G. Gualandi). Cancer Letters 254 (2007) 236–243 www.elsevier.com/locate/canlet