Ultraviolet radiation down-regulates expression of the cell-cycle inhibitor p21(WAF1/CIP1) in human cancer cells independently of p53

Purpose: To investigate the regulation of G1 cyclin-dependent kinase inhibi tor p21(WAF1/CIP1) by ultraviolet (UV) radiation in human carcinoma cells. Materials and methods: Human cancer cell lines were irradiated with UV-C (2 54 nm) radiation, and their responses were characterized by Western blottin g, Northern blotting, semi-quantitative RT-PCR analysis, trypan blue staini ng and flow cytometric cell cycle analysis. Results: Ar 24 h after UV irradiation, p21 expression was down-regulated in various cancer cell types (breast, prostrate, cenix, colon, glioma, squamo us cancers), independently of their p53 genetic and functional status. UV-m ediated down-regulation of p21 was dose- and time-dependent,vas observed at the protein and mRNA levels, and did not correlate with cytotoxicity. Redu ction 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 p 21 levels in these cell lines was due to enhanced proteasomal degradation. Despite decreased p21 levels, UV-irradiated breast cancer cells with wild-t ype 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, suggesti ng a p53-dependent G1 check point in MCF-7. UV treatment caused other alter ations in cell-cycle 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-c ycle inhibitor p21 in tumour cells. It is postulated that this may be an ad aptation to promote the growth and survival of transformed cells.