RADIO-INDUCED MODULATION OF TRANSFORMING GROWTH-FACTOR-BETA-1 SENSITIVITY IN A P53 WILD-TYPE HUMAN COLORECTAL-CANCER CELL-LINE

Unlike normal intestinal cells, colorectal-carcinoma cell lines are us ually not responsive to transforming growth factor beta 1. The cyclin- dependent kinase inhibitor p21 that is induced by X irradiation in cel ls expressing normal p53 can also be induced by TGF-beta 1 by a p53-in dependent pathway. We have investigated possible interactions between ionizing radiation and TGF-beta 1, using a panel of 8 human colorectal -cancer cell lines varying in p53 status and sensitivity to the cyto-i nhibitory effect of TGF-beta 1. Heterogeneity in the radiosensitivity of these cell lines was observed, with SF2 (surviving fraction after i rradiation with 2 Gy) ranging from 0.19 to 0.82. Radioresistance (high SF2 values) was in general associated with abnormal expression of p53 . An effect of TGF-beta 1 treatment on radiosensitivity was observed w ith one cell line only (LS513), and manifested by enhancement of the c ytotoxic effect of radiation. In an experiment with fractionated irrad iation during continuous exposure to TGF-beta 1, there was no change i n the intrinsic radiosensitivity of LS513 cells, though irradiated cel ls treated with TGF-beta 1 were more sensitive to the first radiation dose. Irradiated LS513 colorectal-cancer and Mv-1-Lu epithelial cells were significantly more sensitive to TGF-beta 1 than were unirradiated controls, whereas no change was observed in the TGF-beta 1 sensitivit y of irradiated LS1034 cells. Radio-induced modulation of TGF-beta 1 s ensitivity was transitory and declined before the decline to baseline level of p21 mRNA expression. On the basis of these results, we postul ate that radiation-induced sensitization to TGF-beta 1 occurs in TCF-b eta 1-sensitive cells expressing wild-type p53. (C) 1996 Wiley-Liss, I nc.