Radio-induced modulation of transforming growth factor beta1 sensitivity in a p53 wild-type human colorectal-cancer cell line.
Unlike normal intestinal cells, colorectal-carcinoma cell lines are usually not responsive to transforming growth factor beta1. The cyclin-dependent kinase inhibitor p21 that is induced by X irradiation in cells expressing normal p53 can also be induced by TGF-beta1 by a p53-independent pathway. We have investigated possible interactions between ionizing radiation and TGF-beta1, using a panel of 8 human colorectal-cancer cell lines varying in p53 status and sensitivity to the cyto-inhibitory effect of TGF-beta1. Heterogeneity in the radiosensitivity of these cell lines was observed, with SF2 (surviving fraction after irradiation 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-beta1 treatment on radiosensitivity was observed with one cell line only (LS513), and manifested by enhancement of the cytotoxic effect of radiation. In an experiment with fractionated irradiation during continuous exposure to TGF-beta1, there was no change in the intrinsic radiosensitivity of LS513 cells, though irradiated cells treated with TGF-beta1 were more sensitive to the first radiation dose. Irradiated LS513 colorectal-cancer and Mv-1-Lu epithelial cells were significantly more sensitive to TGF-beta1 than were unirradiated controls, whereas no change was observed in the TGF-beta1 sensitivity of irradiated LS1034 cells. Radio-induced modulation of TGF-beta1 sensitivity was transitory and declined before the decline to baseline level of p21 mRNA expression. On the basis of these results, we postulate that radiation-induced sensitization to TGF-beta1 occurs in TGF-beta1-sensitive cells expressing wild-type p53.
Laboratory of Radiobiology, Harvard School of Public Health, Boston, Massachusetts, USA.
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D002470:Cell Survival; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000532:radiotherapy* / Q000628:therapy; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics; D004848:Epithelium / Q000378:metabolism / Q000528:radiation effects; D015870:Gene Expression; D016158:Genes, p53; D006801:Humans; D007700:Kinetics; D012333:RNA, Messenger / Q000378:metabolism; D011838:Radiation-Sensitizing Agents; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012333:RNA, Messenger; D011838:Radiation-Sensitizing Agents; D016212:Transforming Growth Factor beta