TY  - JOUR
A1  - Lee, Lucas D.
A1  - Pozios, Ioannis
A1  - Liu, Verena
A1  - Nachbichler, Silke B.
A1  - Böhmer, Dirk
A1  - Kamphues, Carsten
A1  - Beyer, Katharina
A1  - Bruns, Christiane J.
A1  - Kreis, Martin E.
A1  - Seeliger, Hendrik
T1  - Thymidine phosphorylase induction by ionizing radiation antagonizes 5-fluorouracil resistance in human ductal pancreatic adenocarcinoma
T2  - Radiation and Environmental Biophysics
N2  - Chemoresistance in pancreatic ductal adenocarcinoma (PDAC) frequently contributes to failure of systemic therapy. While the radiosensitizing properties of 5-fluorouracil (FU) are well known, it is unknown whether ionizing radiation (IR) sensitizes towards FU cytotoxicity. Here, we hypothesize that upregulation of thymidine phosphorylase (TP) by IR reverses FU chemoresistance in PDAC cells. The FU resistant variant of the human PDAC cell line AsPC-1 (FU-R) was used to determine the sensitizing effects of IR. Proliferation rates of FU sensitive parental (FU-S) and FU-R cells were determined by WST-1 assays after low (0.05 Gy) and intermediate dose (2.0 Gy) IR followed by FU treatment. TP protein expression in PDAC cells before and after IR was assessed by Western blot. To analyze the specificity of the FU sensitizing effect, TP was ablated by siRNA. FU-R cells showed a 2.7-fold increase of the half maximal inhibitory concentration, compared to FU-S parental cells. Further, FU-R cells showed a concomitant IR resistance towards both doses applied. When challenging both cell lines with FU after IR, FU-R cells had lower proliferation rates than FU-S cells, suggesting a reversal of chemoresistance by IR. This FU sensitizing effect was abolished when TP was blocked by anti-TP siRNA before IR. An increase of TP protein expression was seen after both IR doses. Our results suggest a TP dependent reversal of FU-chemoresistance in PDAC cells that is triggered by IR. Thus, induction of TP expression by low dose IR may be a therapeutic approach to potentially overcome FU chemoresistance in PDAC.
Y1  - 2022
UR  - https://opus.bibliothek.uni-augsburg.de/opus4/frontdoor/index/index/docId/123804
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:384-opus4-1238044
SN  - 0301-634X
SN  - 1432-2099
VL  - 61
IS  - 2
SP  - 255
EP  - 262
PB  - Springer Science and Business Media LLC
ER  -