Identification of New Mechanisms
of Cellular Response
to Chemotherapy by Tracking Changes in Post-Translational Modifications
by Ubiquitin and Ubiquitin-Like Proteins
posted on 2014-05-02, 00:00authored byThomas 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
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.