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

被引：28

作者：

Bonacci, Thomas ^{[1
]}

Audebert, Stephane ^{[1
]}

Camoin, Luc ^{[1
]}

Baudelet, Emilie ^{[1
]}

Bidaut, Ghislain ^{[1
]}

Garcia, Maxime ^{[1
]}

Witzel, Ini-Isabee ^{[2
]}

Perkins, Neil D. ^{[2
]}

Borg, Jean-Paul ^{[1
]}

Iovanna, Juan-Lucio ^{[1
]}

Soubeyran, Philippe ^{[1
]}

机构：

[1] Aix Marseille Univ, CRCM, Inst J Paoli I Calmettes, CNRS,UMR7258,INSERM,U1068,UM105, F-13009 Marseille, France

[2] Newcastle Univ, Sch Med, Inst Cell & Mol Biosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

来源：

JOURNAL OF PROTEOME RESEARCH | 2014年 / 13卷 / 05期

关键词：

pancreatic cancer; anticancer drugs resistance; gemcitabine; stress response; post-translationnal modification; ubiquitin; ubiquitin-like proteins; Nedd8; SUMO1; MOLECULAR INTERACTION DATABASE; TARGET; NEDD8; UBIQUITYLATION; MODIFIER; SITES; CELLS;

D O I：

10.1021/pr401258d

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：2478 / 2494

页数：17

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