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

J Clin Invest. 2004 Mar;113(6):867-75. doi: 10.1172/JCI20732.

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 alpha-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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carcinoma, Basal Cell / metabolism
  • Carcinoma, Basal Cell / prevention & control*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / prevention & control*
  • Eflornithine / pharmacology
  • Heterozygote
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Ornithine Decarboxylase / metabolism*
  • Ornithine Decarboxylase Inhibitors
  • Patched Receptors
  • Patched-1 Receptor
  • Receptors, Cell Surface
  • Ultraviolet Rays

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Ornithine Decarboxylase Inhibitors
  • PTCH protein, human
  • Patched Receptors
  • Patched-1 Receptor
  • Ptch1 protein, mouse
  • Receptors, Cell Surface
  • Ornithine Decarboxylase
  • Eflornithine