p53-null cells are more sensitive to ultraviolet light only in the presence of caffeine

• Published in: Cancer research (Chicago, Ill.) Vol. 56; no. 23; pp. 5365 - 5368
• Main Authors: DEFRANK, J. S, TANG, W, POWELL, S. N
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.12.1996
• Subjects: Animals; Biological and medical sciences; Caffeine - pharmacology; Carcinogenesis, carcinogens and anticarcinogens; Cell Cycle - drug effects; DNA Repair; Dose-Response Relationship, Drug; Fibroblasts - drug effects; Fibroblasts - radiation effects; Genes, p53; Medical sciences; Mice; Mice, Knockout; Physical agents; Radiation Tolerance; Radiation-Sensitizing Agents - pharmacology; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - physiology; Tumors; Ultraviolet Rays; X-Rays; Embryo; Excision; Rodentia; Cytotoxicity; In vitro; Vertebrata; Ultraviolet radiation; Mammalia; Mouse; Animal; DNA; Sensitization; Xanthine derivatives; Repair; Fibroblast; Caffeine; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445

We have shown previously that p53(-/-) fibroblasts show greater sensitization by caffeine to the lethal effects of ionizing radiation compared with p53(+/+) cells. Recently published data have suggested a possible role of p53 in nucleotide excision repair: an association of p53 and xeroderma pigmentosum group B protein and a greater sensitivity to cisplatin of RKO cells transfected with the E6 protein of human papilloma virus (inactivating p53). We show that p53(+/+) and p53(-/-) cells have equal sensitivity to germicidal UV light (as with ionizing radiation). However, the introduction of 2 mM caffeine led to a sensitization enhancement ratio (at 10% survival) of 1.8 in p53(-/-) cells, but only 1.3 in wild-type (p53+/+) cells. Lower doses of caffeine had less effect, and 0.1 mM caffeine resulted in no detectable sensitization of either cell type to UV light in contrast to X-rays. The differential sensitivity of p53(-/-) cells to X-rays and caffeine was thought to be due to override of the G2-M block to cell cycle progression. In response to UV light, cells accumulate in S phase, and the magnitude of S-phase accumulation was observed to be greater in p53(-/-) cells. Caffeine had little effect on the cell cycle distribution in p53(+/+) cells. However, for p53(-/-) cells, a greater proportion were in S phase after treatment with caffeine, and a complete loss of S-phase delay was observed after UV irradiation. In conclusion, the role of p53 in nucleotide excision repair appears to be of little significance for cell survival. Greater sensitization of p53(-/-) cells to caffeine could be mediated via override of S-phase delay.