<<< Full experiment listing


PXD015284 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleKinase inhibition sensitizes pancreatic cancer cells towards radiation
DescriptionPancreatic ductal adenocarcinoma is one of the most aggressive cancer types and is well-known for its general low intrinsic radiosensitivity. In order to resolve mechanisms of how PDAC cells carry out radioresistance, a combination of proteomics and phosphoproteomics of two radiosensitive as well as radioresistant murine PDAC cell lines upon exposition to radiation was performed. A high depth of (phospho)proteomic identifications with > 13000 confidently identified phosphorylation sites and > 7800 proteins was achieved. Measuring the response of the phosphoproteome upon radiation revealed >700 phosphorylation sites on >400 proteins which were regulated in all four cell lines independently of the sensitivity status. This analysis validated already known radiomarkers but also uncovered novel members of the radiation-dependent signaling network in PDAC cells that were shown to be exclusively based on protein phosphorylation but not protein expression. Among those radioresponsive phosphoproteins were ten novel ATM substrates, which were validated by in vitro kinase assays. Comparison of radiosensitive and -resistant cells revealed a complex regulation of apoptotic processes, while changes in expression of DNA repair proteins seemed to not play a pivotal role. Especially increased expression of NQO1 was found to be a potential mechanism enabling resistance by clearing harmful reactive oxygen species from the PDAC cells. Further analysis of the radioresistance-associated-phosphoproteome, which was especially enriched in phosphoproteins with cytoskeleton organizational function, uncovered increased Actin dynamics and FAK activity in radioresistant cells. Both likely lead to increased survival, migrational capacity and perturbations in chromatin condensation which could oppose radiation. Based on the displayed adaptions in cellular protein expression and signaling in resistant PDAC cells, pharmacological inhibition of NQO1 and FAK could be suggested to sensitize towards radiation.
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterSvenja Wiechmann
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationListphosphorylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02019-09-02 07:39:14ID requested
12020-07-16 22:41:01announced
Publication List
Wiechmann S, Saupp E, Schilling D, Heinzlmeir S, Schneider G, Schmid RM, Combs SE, Kuster B, Dobiasch S, Radiosensitization by Kinase Inhibition Revealed by Phosphoproteomic Analysis of Pancreatic Cancer Cells. Mol Cell Proteomics, 19(10):1649-1663(2020) [pubmed]
Keyword List
submitter keyword: PDAC, pancreatic cancer, phosphoproteomics
Contact List
Bernhard Kuster
contact affiliationChair of Proteomics and Bioanalytics Technische Universitaet Muenchen Partner Site of the German Cancer Consortium Emil Erlenmeyer Forum 5 85354 Freising Germany
contact emailkuster@tum.de
lab head
Svenja Wiechmann
contact affiliationTU Munich, Proteomics and Bioanalytics
contact emailsvenja.wiechmann@tum.de
dataset submitter
Full Dataset Link List
Dataset FTP location
PRIDE project URI
Repository Record List
[ + ]