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1
* Department of Human Pathology, University of Messina, Messina, Italy;
Institute of Experimental Pathology, University of Ancona, Italy;
Department of Medicine and Aging, University ‘G. D’Annunzio’, Chieti, Italy;
|| DNA Unit Hospital Clinic, Barcelona, Spain; and
¶ Department of Pathology, City Hospital, Alessandria, Italy
1Correspondence: Dipartimento di Medicina e Scienze dell’Invecchiamento, Cattedra di Ematologia, Università ‘G. D’Annunzio’, Via dei Vestini, 31, 66013, Chieti, Italy. E-mail: mromano{at}unich.it
Evidence indicates that lipoxygenases (LO) may play a role in cancer cell survival. We show that human malignant pleural mesothelial (MM) cells, but not normal mesothelial (NM) cells, express a catalytically active 5-LO. Pharmacological or genetic inhibition of MM cell 5-LO determined nucleosome formation and induced a DNA fragmentation pattern typical of apoptosis. This was completely reversed by exogenously added 5(S)-HETE but not by 12(S)-, 15(S)-HETE, or leukotriene (LT)B4. A 5-LO antisense oligonucleotide potently and time-dependently reduced vascular endothelial growth factor (VEGF) mRNA and constitutive VEGF accumulation in the conditioned media of MM cells. When NM cells were transfected with a 5-LO cDNA, basal and arachidonic acid-induced VEGF formation increased consistently by 6- and 12-fold, respectively. This was associated with a significant increase in DNA synthesis that was counteracted by a specific anti-VEGF antibody. Arachidonic acid and 5(S)-HETE also potently stimulated the activity of a VEGF promoter construct. Thus, 5-LO is a key regulator of MM cell proliferation and survival via a VEGF-related circuit.—Romano, M., Catalano, A., Nutini, M., D’Urbano, E., Crescenzi, C., Claria, J., Libner, R., Davi, G., Procopio, A. 5-Lipoxygenase regulates malignant mesothelial cell survival: involvement of vascular endothelial growth factor.
Key Words: mesothelioma • arachidonic acid • apoptosis • angiogenesis • eicosanoids
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