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
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.