5‐Lipoxygenase regulates malignant mesothelial cell survival: involvement of vascular endothelial growth factor

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)B 4 . A 5‐LO antisense oligo‐nucleotide 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. FASEB J . 15, 2326–2336 (2001)