cp-31398 and Skin-Neoplasms

Chronic exposure to UV light is a risk factor for skin cancer in which signature mutations in the p53 tumor suppressor gene occur due to DNA damage and contribute to cancer development. In this issue of the JCI, Tang et al. report on their study of a nonimmunodeficient mouse model of UVB-induced skin cancer and human skin carcinoma cells and show that the mutant p53 conformation-modifying drug CP-31398 not only treats these tumors but also prevents them (see the related article beginning on page 3753). These studies have important implications for chemoprevention as well as therapy of common, mutant p53-driven tumors.

Topics: Animals; Apoptosis; bcl-X Protein; Caspase 3; Cell Line, Tumor; Cell Transformation, Neoplastic; Cyclin D; Cyclins; Cytochromes c; Environmental Exposure; Female; Humans; Male; Mice; Mice, Hairless; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Mutation; Neoplasms, Radiation-Induced; Poly(ADP-ribose) Polymerases; Proliferating Cell Nuclear Antigen; Protein Transport; Pyrimidines; Skin Neoplasms; Tumor Suppressor Protein p53; Ultraviolet Rays

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.

Topics: Animals; Apoptosis; bcl-X Protein; Caspase 3; Cell Line, Tumor; Cell Transformation, Neoplastic; Cyclin D; Cyclins; Cytochromes c; Environmental Exposure; Female; Humans; Male; Mice; Mice, Hairless; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Mutation; Neoplasms, Radiation-Induced; Poly(ADP-ribose) Polymerases; Proliferating Cell Nuclear Antigen; Protein Transport; Pyrimidines; Skin Neoplasms; Tumor Suppressor Protein p53; Ultraviolet Rays

Topics: Apoptosis; Humans; Melanoma; Pyrimidines; Skin Neoplasms; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Ultraviolet Rays