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Open Access Green as soon as Postprint is submitted to ZB.
Identification of the unfolded protein response pathway as target for radiosensitization in pancreatic cancer.
Radiother. Oncol. 191:110059 (2024)
BACKGROUND AND PURPOSE: Due to the high intrinsic radioresistance of pancreatic ductal adenocarcinoma (PDAC), radiotherapy (RT) is only beneficial in 30% of patients. Therefore, this study aimed to identify targets to improve the efficacy of RT in PDAC. MATERIALS AND METHODS: Alamar Blue proliferation and colony formation assay (CFA) were used to determine the radioresponse of a cohort of 38 murine PDAC cell lines. A gene set enrichment analysis was performed to reveal differentially expressed pathways. CFA, cell cycle distribution, γH2AX FACS analysis, and Caspase 3/7 SYTOX assay were used to examine the effect of a combination treatment using KIRA8 as an IRE1α-inhibitor and Ceapin-A7 as an inhibitor against ATF6. RESULTS: The unfolded protein response (UPR) was identified as a pathway highly expressed in radioresistant cell lines. Using the IRE1α-inhibitor KIRA8 or the ATF6-inhibitor Ceapin-A7 in combination with radiation, a radiosensitizing effect was observed in radioresistant cell lines, but no substantial alteration of the radioresponse in radiosensitive cell lines. Mechanistically, increased apoptosis by KIRA8 in combination with radiation and a cell cycle arrest in the G1 phase after ATF6 inhibition and radiation have been observed in radioresistant cell lines. CONCLUSION: So, our data show evidence that the UPR is involved in radioresistance of PDAC. Increased apoptosis and a G1 cell cycle arrest seem to be responsible for the radiosensitizing effect of UPR inhibition. These findings are supportive for developing novel combination treatment concepts in PDAC to overcome radioresistance.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Atf6 ; Ire1α ; Pancreatic Ductal Adenocarcinoma ; Radiosensitization ; Radiotherapy ; Unfolded Protein Response
ISSN (print) / ISBN
0167-8140
e-ISSN
1879-0887
Journal
Radiotherapy and Oncology
Quellenangaben
Volume: 191,
Article Number: 110059
Publisher
Elsevier
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Radiation Medicine (IRM)