5-lipoxygenase regulates malignant mesothelial cell survival: involvement of vascular endothelial growth factor

Citation
M. Romano et al., 5-lipoxygenase regulates malignant mesothelial cell survival: involvement of vascular endothelial growth factor, FASEB J, 15(13), 2001, pp. 2326-2336
Citations number
39
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Experimental Biology
Journal title
FASEB JOURNAL
ISSN journal
0892-6638 → ACNP
Volume
15
Issue
13
Year of publication
2001
Pages
2326 - 2336
Database
ISI
SICI code
0892-6638(200111)15:13<2326:5RMMCS>2.0.ZU;2-Z
Abstract
Evidence indicates that lipoxygenases (LO) may play a role in cancer cell s urvival. We show that human malignant pleural mesothelial (MM) cells, but n ot normal mesothelial (NM) cells, express a catalytically active 5-LO. Phar macological or genetic inhibition of MM cell 5-LO determined nucleosome for mation and induced a DNA fragmentation pattern typical of apoptosis. This w as 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 oligonucleotide potently and time-dependently reduced vascular endothelial growth factor (VEGF) mRN A 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, respectiv ely. 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 V EGF-related circuit.