Universität zu Köln

Lee, Lucas D. ORCID: 0000-0001-5729-0537, Pozios, Ioannis ORCID: 0000-0002-3462-9822, Liu, Verena, Nachbichler, Silke B., Boehmer, Dirk, Kamphues, Carsten ORCID: 0000-0002-5406-8540, Beyer, Katharina, Bruns, Christiane J., Kreis, Martin E. ORCID: 0000-0002-9312-4840 and Seeliger, Hendrik ORCID: 0000-0002-5937-052X (2022). Thymidine phosphorylase induction by ionizing radiation antagonizes 5-fluorouracil resistance in human ductal pancreatic adenocarcinoma. Radiat. Environ. Biophys., 61 (2). S. 255 - 263. NEW YORK: SPRINGER. ISSN 1432-2099

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Lee, Lucas D. UNSPECIFIED orcid.org/0000-0001-5729-0537 UNSPECIFIED Pozios, Ioannis UNSPECIFIED orcid.org/0000-0002-3462-9822 UNSPECIFIED Liu, Verena UNSPECIFIED UNSPECIFIED UNSPECIFIED Nachbichler, Silke B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boehmer, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Kamphues, Carsten UNSPECIFIED orcid.org/0000-0002-5406-8540 UNSPECIFIED Beyer, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruns, Christiane J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kreis, Martin E. UNSPECIFIED orcid.org/0000-0002-9312-4840 UNSPECIFIED Seeliger, Hendrik UNSPECIFIED orcid.org/0000-0002-5937-052X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-683963
DOI:	10.1007/s00411-022-00962-w
Journal or Publication Title:	Radiat. Environ. Biophys.
Volume:	61
Number:	2
Page Range:	S. 255 - 263
Date:	2022
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-2099
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CANCER; CELLS; CHEMOTHERAPY; RADIOTHERAPY; GEMCITABINE; INHIBITION; FOLFIRINOX; ACTIVATION; EXPRESSION Multiple languages Biology; Biophysics; Environmental Sciences; Radiology, Nuclear Medicine & Medical Imaging Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68396