PXD015284

PXD015284 is an original dataset announced via ProteomeXchange.

Title	Kinase inhibition sensitizes pancreatic cancer cells towards radiation
Description	Pancreatic 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.
HostingRepository	PRIDE
AnnounceDate	2020-07-17
AnnouncementXML	Submission_2020-07-16_22:41:00.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Svenja Wiechmann
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-09-02 07:39:14	ID requested
⏵ 1	2020-07-16 22:41:01	announced

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]

submitter keyword: PDAC, pancreatic cancer, phosphoproteomics

Bernhard Kuster
contact affiliation	Chair of Proteomics and Bioanalytics Technische Universitaet Muenchen Partner Site of the German Cancer Consortium Emil Erlenmeyer Forum 5 85354 Freising Germany
contact email	kuster@tum.de
lab head
Svenja Wiechmann
contact affiliation	TU Munich, Proteomics and Bioanalytics
contact email	svenja.wiechmann@tum.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/07/PXD015284

PRIDE project URI

• PRIDE
  1. PXD015284
     1. Label: PRIDE project
     2. Name: Kinase inhibition sensitizes pancreatic cancer cells towards radiation