Ultraviolet radiation down-regulates expression of the cell-cycle inhibitor p21WAF1/CIP1 in human cancer cells independently of p53

Abstract

Purpose : To investigate the regulation of G1 cyclin-dependent kinase inhibitor p21WAF1/CIP1 by ultraviolet (UV) radiation in human carcinoma cells. Materials and methods : Human cancer cell lines were irradiated with UV-C (254nm) radiation, and their responses were characterized by Western blotting, Northern blotting, semi-quantitative RT-PCR analysis, trypan blue staining and flow cytometric cell cycle analysis. Results : At 24 h after UV irradiation, p21 expression was downregulated in various cancer cell types (breast, prostrate, cervix, colon, glioma, squamous cancers), independently of their p53 genetic and functional status. UV-mediated down-regulation of p21 was dose- and time-dependent, was observed at the protein and mRNA levels, and did not correlate with cytotoxicity. Reduction of p21 protein levels required about 4 and 1 h, respectively, in MCF-7 and MDA-MB-231 breast cancer cells; some of the UV-induced decreases in p21 levels in these cell lines was due to enhanced proteasomal degradation. Despite decreased p21 levels, UV-irradiated breast cancer cells with wildtype p53 (MCF-7) retained the capacity for G1 cell-cycle arrest, whereas UV-treated cells with mutant p53 (MDA-MB-231) accumulated in S phase, suggesting a p53-dependent G1 checkpoint in MCF-7. UV treatment caused other alterations in cellcycle regulatory, DNA repair and tumour suppressor genes, as described in this report. Conclusions : In contrast to X-rays, UV causes down-regulation of the cell-cycle inhibitor p21 in tumour cells. It is postulated that this may be an adaptation to promote the growth and survival of transformed cells.