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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)867-875
Number of pages9
JournalJournal of Clinical Investigation
Volume113
Issue number6
DOIs
StatePublished - Mar 1 2004

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Ornithine Decarboxylase
Basal Cell Carcinoma
Chemoprevention
Squamous Cell Carcinoma
Keratin-6
Carcinogenesis
Eflornithine
Skin
Hair Follicle
Polyamines
Enzymes
Tumor Suppressor Genes
Oral Administration
Radiation
Mutation
Population

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Tang, Xiuwei ; Kim, Arianna L. ; Feith, David J. ; Pegg, Anthony E. ; Russo, Justin ; Zhang, Hong ; Aszterbaum, Michelle ; Kopelovich, Levy ; Epstein, Ervin H. ; Bickers, David R. ; Athar, Mohammad. / Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/- mice. In: Journal of Clinical Investigation. 2004 ; Vol. 113, No. 6. pp. 867-875.
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title = "Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/- mice",
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.",
author = "Xiuwei Tang and Kim, {Arianna L.} and Feith, {David J.} and Pegg, {Anthony E.} and Justin Russo and Hong Zhang and Michelle Aszterbaum and Levy Kopelovich and Epstein, {Ervin H.} and Bickers, {David R.} and Mohammad Athar",
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Tang, X, Kim, AL, Feith, DJ, Pegg, AE, Russo, J, Zhang, H, Aszterbaum, M, Kopelovich, L, Epstein, EH, Bickers, DR & Athar, M 2004, 'Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/- mice', Journal of Clinical Investigation, vol. 113, no. 6, pp. 867-875. https://doi.org/10.1172/JCI200420732

Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/- mice. / Tang, Xiuwei; Kim, Arianna L.; Feith, David J.; Pegg, Anthony E.; Russo, Justin; Zhang, Hong; Aszterbaum, Michelle; Kopelovich, Levy; Epstein, Ervin H.; Bickers, David R.; Athar, Mohammad.

In: Journal of Clinical Investigation, Vol. 113, No. 6, 01.03.2004, p. 867-875.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ornithine decarboxylase is a target for chemoprevention of basal and squamous cell carcinomas in Ptch1+/- mice

AU - Tang, Xiuwei

AU - Kim, Arianna L.

AU - Feith, David J.

AU - Pegg, Anthony E.

AU - Russo, Justin

AU - Zhang, Hong

AU - Aszterbaum, Michelle

AU - Kopelovich, Levy

AU - Epstein, Ervin H.

AU - Bickers, David R.

AU - Athar, Mohammad

PY - 2004/3/1

Y1 - 2004/3/1

N2 - 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.

AB - 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.

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