15-Lipoxygenase-1 induces lipid peroxidation and apoptosis, and improves survival in rat malignant glioma.
BACKGROUND
Previous studies suggest either an anti- or pro-apoptotic role for 15-lipoxygenase-1 in carcinogenesis.


METHODS
We used adenovirus gene transfer of human 15-lipoxygenase-1 to characterize its effects in vitro and in vivo.


RESULTS
15-Lipoxygenase-1 expression in mouse macrophages resulted in a significant, 25-fold, induction in the production of the specific 15-lipoxygenase-1 product 13-hydroxyoctadecadienoic acid. Tail vein gene transfers in mice led to highest expression of the transduced 15-lipoxygenase-1 in liver and spleen. In the liver, 15-lipoxygenase-1 significantly increased lipid peroxidation by 3.5-fold and 2-fold, three and seven days after transduction, respectively. A significant 32-fold induction in caspase-3 activity was detected in 15-lipoxygenase-1 expressing livers seven days after transduction. In a syngeneic rat model of malignant glioma, 15-lipoxygenase-1 extended survival significantly (p=0.001).


CONCLUSIONS
Our results support the pro-apoptotic role of 15-lipoxygenase-1 and suggest that 15-lipoxygenase-1 could be a potential new target gene for the therapy of malignant glioma.
Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
Helena
H
Viita
Agnieszka
A
Pacholska
Farizan
F
Ahmad
Johanna
J
Tietäväinen
Jonne
J
Naarala
Anna
A
Hyvärinen
Thomas
T
Wirth
Seppo
S
Ylä-Herttuala
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008041:Linoleic Acids / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D051381:Rats; D013154:Spleen / Q000201:enzymology / Q000378:metabolism; D016019:Survival Analysis; D047368:Tumor Burden
D008041:Linoleic Acids; C024348:13-hydroxy-9,11-octadecadienoic acid; D001093:Arachidonate 15-Lipoxygenase