title: Identification of new mechanisms of cellular response to chemotherapy by tracking changes in post-translational modifications by ubiquitin and ubiquitin-like proteins.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive malignancy characterized by an excessive resistance to all known anticancer therapies, a still largely elusive phenomenon. To identify original mechanisms, we have explored the role of post-translational modifications (PTMs) mediated by members of the ubiquitin family. Although alterations of these pathways have been reported in different cancers, no methodical search for these kinds of anomalies has been performed so far. Therefore, we studied the ubiquitin-, Nedd8-, and SUMO1-specific proteomes of a pancreatic cancer cell line (MiaPaCa-2) and identified changes induced by gemcitabine, the standard PDAC's chemotherapeutic drug. These PTMs profiles contained both known major substrates of all three modifiers as well as original ones. Gemcitabine treatment altered the PTM profile of proteins involved in various biological functions, some known cancer associated genes, many potentially cancer-associated genes, and several cancer-signaling networks, including canonical and noncanonical WNT and PI3K/Akt/MTOR pathways. Some of these altered PTMs formed groups of functionally and physically associated proteins. Importantly, we could validate the gemcitabine-induced PTMs variations of relevant candidates and we could demonstrate the biological significance of such altered PTMs by studying in detail the sumoylation of SNIP1, one of these new targets.
authors.affiliation: CRCM, INSERM U1068; Institut Paoli-Calmettes; Aix-Marseille Université, UM105; CNRS, UMR7258, 163 Av de Luminy, F-13009 Marseille, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bonacci
authors.forename: Stéphane
authors.initials: S
authors.lastname: Audebert
authors.forename: Luc
authors.initials: L
authors.lastname: Camoin
authors.forename: Emilie
authors.initials: E
authors.lastname: Baudelet
authors.forename: Ghislain
authors.initials: G
authors.lastname: Bidaut
authors.forename: Maxime
authors.initials: M
authors.lastname: Garcia
authors.forename: Ini-Isabée
authors.initials: II
authors.lastname: Witzel
authors.forename: Neil D
authors.initials: ND
authors.lastname: Perkins
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Borg
authors.forename: Juan-Lucio
authors.initials: JL
authors.lastname: Iovanna
authors.forename: Philippe
authors.initials: P
authors.lastname: Soubeyran
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D000075687:NEDD8 Protein; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011506:Proteins / Q000378:metabolism*; D020543:Proteome / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016601:RNA-Binding Proteins; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism; D051155:Wnt1 Protein / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D047908:Intracellular Signaling Peptides and Proteins; D000075687:NEDD8 Protein; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D020543:Proteome; D051057:Proto-Oncogene Proteins c-akt; D016601:RNA-Binding Proteins; D025842:SUMO-1 Protein; D058570:TOR Serine-Threonine Kinases; D025801:Ubiquitin; D014452:Ubiquitins; D051155:Wnt1 Protein; D000093542:Gemcitabine; C082860:NEDD8 protein, human; C411545:SNIP1 protein, human; C495501:SUMO1 protein, human; C546842:MTOR protein, human