Identification of new mechanisms of cellular response to chemotherapy by tracking changes in post-translational modifications by ubiquitin and ubiquitin-like proteins

Thomas Bonacci, Stéphane Audebert, Luc Camoin, Emilie Baudelet, Ghislain Bidaut, Maxime Garcia, Ini Isabée Witzel, Neil D. Perkins, Jean Paul Borg, Juan Lucio Iovanna, Philippe Soubeyran

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2478-2494
Number of pages17
JournalJournal of Proteome Research
Volume13
Issue number5
DOIs
StatePublished - May 2 2014

Keywords

  • Nedd8
  • SUMO1
  • anticancer drugs resistance
  • gemcitabine
  • pancreatic cancer
  • post-translationnal modification
  • stress response
  • ubiquitin
  • ubiquitin-like proteins

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

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