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Identification of New Mechanisms of Cellular Response to Chemotherapy by Tracking Changes in Post-Translational Modifications by Ubiquitin and Ubiquitin-Like Proteins

Lookup NU author(s): Professor Neil PerkinsORCiD

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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 SNIP!, one of these new targets.

Publication metadata

Author(s): Bonacci T, Audebert S, Camoin L, Baudelet E, Bidaut G, Garcia M, Witzel II, Perkins ND, Borg JP, Iovanna JL, Soubeyran P

Publication type: Article

Publication status: Published

Journal: Journal of Proteome Research

Year: 2014

Volume: 13

Issue: 5

Pages: 2478-2494

Print publication date: 01/05/2014

Online publication date: 21/03/2014

Acceptance date: 17/12/2013

ISSN (print): 1535-3893

ISSN (electronic): 1535-3907

Publisher: American Chemical Society

URL: http://dx.doi.org/10.1021/pr401258d

DOI: 10.1021/pr401258d

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