Targeted antizyme expression in the skin of transgenic mice reduces tumor promoter induction of ornithine decarboxylase and decreases sensitivity to chemical carcinogenesis.
To directly evaluate the role of increased ornithine decarboxylase (ODC) and polyamines in mouse skin carcinogenesis, we used bovine keratin 5 (K5) and keratin 6 (K6) promoter elements to direct the expression of antizyme (AZ) to specific skin cell populations. AZ is a multifunctional regulator of polyamine metabolism that inhibits ODC activity, stimulates ODC degradation, and suppresses polyamine uptake. K5-AZ mice treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) at 0 and 24 h exhibit increases in epidermal and dermal ODC activity that are reduced in magnitude. K6-AZ mice treated similarly do not show any increased ODC activity or protein after a second application due to TPA-induced expression of AZ protein. Epidermal and dermal polyamine content, particularly spermidine, is reduced in untreated K5-AZ mice and TPA-treated K5-AZ and K6-AZ mice. Susceptibility to 7,12-dimethylbenz(a)anthracene/TPA carcinogenesis was also investigated for two K6-AZ transgenic lines [K6-AZ(52) and K6-AZ(18)] and a single K5-AZ line. K6-AZ(52) mice had a substantial delay in tumor onset and a >80% reduction in tumor multiplicity compared with normal littermates. K6-AZ(18) and K5-AZ mice also developed fewer papillomas than littermate controls (35% and 50%, respectively), and the combination of these lines to produce double transgenic animals yielded an additive decrease (70%) in tumor multiplicity. These mice demonstrate for the first time that AZ suppresses tumor growth in an animal cancer model and provide a valuable model system to evaluate the role of ODC and polyamines in skin tumorigenesis.
Feith
D J
DJ
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Shantz
L M
LM
Pegg
A E
AE
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity; D002417:Cattle; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000378:metabolism; D053569:Keratin-15; D053555:Keratin-5; D007633:Keratins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009955:Ornithine Decarboxylase / Q000096:biosynthesis / Q000235:genetics; D065108:Ornithine Decarboxylase Inhibitors; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D015317:Biogenic Polyamines; D002273:Carcinogens; D004791:Enzyme Inhibitors; D053569:Keratin-15; D053555:Keratin-5; C492053:Krt15 protein, mouse; D065108:Ornithine Decarboxylase Inhibitors; D011506:Proteins; C031017:ornithine decarboxylase antizyme; D015127:9,10-Dimethyl-1,2-benzanthracene; D007633:Keratins; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate