O-phospho-L-tyrosine protects TP53 wild-type cells against ionizing radiation.
O-phospho-L-tyrosine (P-Tyr) has been reported previously to inhibit growth of several cancer cell lines at mM concentrations. In the present study, we investigated the effect of this compound on tumor cells and normal cells in combination with radiation exposure. It could be demonstrated for the first time that P-Tyr at microM concentrations protects TP53 wild-type cells against ionizing radiation (SF4 minus BBI = 0.28, SF4 plus BBI = 0.45). On the contrary, human transformed or tumor cell lines characterized by mutated or functional inactivated TP53 were not altered or increased in their radiation sensitivity (SF4 minus BBI = 0.32, SF4 plus BBI = 0.22). Treatment of wild-type TP53 cells with P-Tyr induced stabilization of TP53 within 3 and 16 hours and a subsequent increase in CDKN1A expression after treatment. Consequently, a 16-hours pretreatment of cells with P-Tyr led to a significant radioprotective effect. This was not observed in cell lines with mutated TP53, which shows no radioprotection by P-Tyr. Thus, the present data suggest that P-Tyr-mediated radioprotection is dependent on preirradiation stabilization of TP53. The results indicate that P-Tyr is a radioprotective agent that can potentially be very useful and easy to deliver for radiation protection in general and especially in radiation therapy of TP53-mutated tumors.
Dittmann
K H
KH
Section of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, Eberhard-Karls-University, Tübingen, Germany. klaus.dittmann@uni-tuebingen.de
Mayer
C
C
Rodemann
H P
HP
D015153:Blotting, Western; D002461:Cell Line, Transformed; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000532:radiotherapy*; D019000:Phosphotyrosine / Q000627:therapeutic use*; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018076:DNA, Complementary; D011837:Radiation-Protective Agents; D016159:Tumor Suppressor Protein p53; D019000:Phosphotyrosine; D013912:Threonine; D012694:Serine