CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice

J Clin Invest. 2007 Dec;117(12):3753-64. doi: 10.1172/JCI32481.

Abstract

Mutations in the tumor suppressor p53 are detectable in over 50% of all human malignancies. Mutant p53 protein is incapable of transactivating its downstream target genes that are required for DNA repair and apoptosis. Chronic exposure to UVB induces p53 mutations and is carcinogenic in both murine and human skin. CP-31398, a styrylquinazoline compound, restores the tumor suppressor functions of mutant forms of p53 in tumor cells. However, its effectiveness in vivo remains unclear. Here, we demonstrate that CP-31398 blocked UVB-induced skin carcinogenesis and was associated with increases in p53, p21, and BclXs. CP-31398 downregulated Bcl2, proliferating nuclear cell antigen, and cyclin D1. Activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase also occurred in both tumor and perilesional skin following treatment. CP-31398 induced the expression of p53-dependent target proteins, and this was followed by apoptosis in UVB-irradiated wild-type mice but not in their p53-deficient littermates. Similar effects were observed in human skin carcinoma A431 cells expressing mutant p53. In addition, CP-31398 induced mitochondrial translocation of p53, leading to changes in mitochondrial membrane permeability pore transition (MPT) and consequent cytochrome c release in these cells. Blocking MPT diminished p53 translocation and apoptosis. These studies indicate that reconstituting p53 tumor suppressor functions in vivo by small molecular weight compounds may block the pathogenesis and progression of skin cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / radiation effects
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / drug effects*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cell Transformation, Neoplastic / radiation effects
  • Cyclin D
  • Cyclins / genetics
  • Cyclins / metabolism
  • Cytochromes c / genetics
  • Cytochromes c / metabolism
  • Environmental Exposure / adverse effects*
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Hairless
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mitochondrial Membrane Transport Proteins / antagonists & inhibitors
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mutation / drug effects
  • Mutation / radiation effects*
  • Neoplasms, Radiation-Induced / drug therapy*
  • Neoplasms, Radiation-Induced / genetics
  • Neoplasms, Radiation-Induced / metabolism
  • Neoplasms, Radiation-Induced / pathology
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proliferating Cell Nuclear Antigen / genetics
  • Proliferating Cell Nuclear Antigen / metabolism
  • Protein Transport / drug effects
  • Protein Transport / genetics
  • Protein Transport / radiation effects
  • Pyrimidines / pharmacology*
  • Pyrimidines / therapeutic use
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ultraviolet Rays / adverse effects*
  • bcl-X Protein / genetics
  • bcl-X Protein / metabolism

Substances

  • BCL2L1 protein, human
  • Bcl2l1 protein, mouse
  • Cyclin D
  • Cyclins
  • Mitochondrial Membrane Transport Proteins
  • Proliferating Cell Nuclear Antigen
  • Pyrimidines
  • Tumor Suppressor Protein p53
  • bcl-X Protein
  • mitochondrial permeability transition pore
  • Cytochromes c
  • Poly(ADP-ribose) Polymerases
  • Casp3 protein, mouse
  • Caspase 3
  • CP 31398