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Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/– mice
Xiuwei Tang, … , David R. Bickers, Mohammad Athar
Xiuwei Tang, … , David R. Bickers, Mohammad Athar
Published March 15, 2004
Citation Information: J Clin Invest. 2004;113(6):867-875. https://doi.org/10.1172/JCI20732.
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Article Dermatology

Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/– mice

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Abstract

Solar ultraviolet B (UVB) radiation induces cutaneous ornithine decarboxylase (ODC), the first enzyme in the polyamine-biosynthesis pathway, which drives continued proliferation and clonal expansion of initiated (mutated) cells, leading to tumorigenesis. Therefore ODC is a potentially important target for chemoprevention of basal cell carcinomas (BCCs), the majority of which have mutations in the tumor-suppressor gene known as patched (PTCH). To assess this possibility, we first overexpressed ODC in the skin of Ptch1+/– mice using a keratin 6 (K6) promoter that directs constitutive ODC expression in the outer root sheath of the hair follicle. UVB irradiation of these mice accelerated induction of BCCs as compared with their Ptch1+/– littermates. To further verify the role of ODC in BCC tumorigenesis, we used an antizyme (AZ) approach to inhibit ODC activity in the Ptch1+/– mice. Ptch1+/– mice with AZ overexpression driven by the K6 promoter were resistant to the induction of BCCs by UVB. Furthermore, oral administration of the suicidal ODC inhibitor α-difluoromethylornithine reduced UVB-induced BCCs in Ptch1+/– mice. These results demonstrate the crucial importance of ODC for the induction of BCCs and indicate that chemopreventive strategies directed at inhibiting this enzyme may be useful in reducing BCCs in human populations.

Authors

Xiuwei Tang, Arianna L. Kim, David J. Feith, Anthony E. Pegg, Justin Russo, Hong Zhang, Michelle Aszterbaum, Levy Kopelovich, Ervin H. Epstein Jr., David R. Bickers, Mohammad Athar

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Figure 1

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Ptch1+/+ heterozygous mice overexpressing ODC (Ptch1+/–/ODC TgN mice). (...
Ptch1+/+ heterozygous mice overexpressing ODC (Ptch1+/–/ODC TgN mice). (A) Ptch1+/– heterozygous mouse. (B) Ptch1+/– heterozygous mouse showing skull abnormality. (C) Ptch1+/–/ODC TgN mouse. (D) Ptch1+/–/ODC TgN mouse showing skull abnormality. (E) Ptch1+/–/ODC TgN mouse at week 10. (F) Ptch1+/–/ODC TgN mouse at week 30. (G) UVB-irradiated Ptch1+/–/ODC TgN mouse at week 10. (H) UVB-irradiated Ptch1+/–/ODC TgN mouse at week 20. (I) UVB-irradiated Ptch1+/–/ODC TgN mouse at week 30
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