Inhibition of carcinogenesis in transgenic mouse models over-expressing 15-lipoxygenase in the vascular wall under the control of murine preproendothelin-1 promoter.
Oxygenases are a family of enzymes that dioxygenate unsaturated fatty acids, thus initiating membrane oxidation and signaling molecule synthesis. The lipoxygenases (LOs), a family of lipid-peroxidizing enzymes that induce structural and metabolic changes in the cell in a number of pathophysiological conditions, belong to the oxygenases family. This class of enzymes has several subgroups, named 5-, 8-, 12- and 15-LOs, and these LO-isoforms are capable of oxygenating arachidonic and linoleic acid. 15-LOs were reported to play an inhibitory role in tumor angiogenesis and, consequently, they slow down carcinogenesis. It has been suggested that its anti-carcinogenic effect is conferred by promoting cell differentiation and apoptosis. Using transgenic mice that over-express 15-LO-1 in endothelial cells under the regulation of the murine preproendothelin-1 promoter, we studied its effect on tumor and metastasis growth. We found that 15-LO-1 inhibited tumor and metastasis growth in the transgenic mice in two different models of cancer (mammary gland and Lewis lung carcinoma). This inhibition was concomitant with a higher number of apoptotic cells in the metastases of the transgenic mice and with a complicated network of multiple small blood vessels. This finding targets 15-LO as a new candidate in the treatment of carcinogenesis.
Harats
Dror
D
Institute of Lipid and Atherosclerosis Research, Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, 52621 Hashomer Tel, Israel. dharats@post.tau.ac.il
Ben-Shushan
Dikla
D
Cohen
Hofit
H
Gonen
Ayelet
A
Barshack
Iris
I
Goldberg
Iris
I
Greenberger
Shoshana
S
Hodish
Israel
I
Harari
Ayelet
A
Varda-Bloom
Nira
N
Levanon
Keren
K
Grossman
Ehud
E
Chaitidis
Pavlos
P
Kühn
Hartmut
H
Shaish
Aviv
A
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001808:Blood Vessels; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000235:genetics / Q000503:physiopathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019332:Endothelin-1 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000235:genetics / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015854:Up-Regulation
D019332:Endothelin-1; D001093:Arachidonate 15-Lipoxygenase