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PML hyposumoylation is responsible for the resistance of pancreatic cancer
Author(s) -
Swayden Mirna,
Alzeeb George,
Masoud Rawand,
Berthois Yolande,
Audebert Stéphane,
Camoin Luc,
Hannouche Laurent,
Vachon Hortense,
Gayet Odile,
Bigonnet Martin,
Roques Julie,
Silvy Françoise,
Carrier Alice,
Dusetti Nelson,
Iovanna Juan L.,
Soubeyran Philippe
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201901091r
Subject(s) - sumo protein , neddylation , cancer research , pancreatic cancer , promyelocytic leukemia protein , ubiquitin , gemcitabine , biology , drug resistance , ubiquitin ligase , cancer , cell culture , chemistry , acute promyelocytic leukemia , genetics , retinoic acid , gene
The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is mainly due to its rapidly acquired resistance to all conventional treatments. Despite drug‐specific mechanisms of resistance, none explains how these cells resist the stress induced by any kind of anticancer treatment. Activation of stress‐response pathways relies on the post‐translational modifications (PTMs) of involved proteins. Among all PTMs, those mediated by the ubiquitin family of proteins play a central role. Our aim was to identify alterations of ubiquitination, neddylation, and sumoylation associated with the multiresistant phenotype and demonstrate their implications in the survival of PDAC cells undergoing treatment. This approach pointed at an alteration of promyelocytic leukemia (PML) protein sumoylation associated with both gemcitabine and oxaliplatin resistance. We could show that this alteration of PML sumoylation is part of a general mechanism of drug resistance, which in addition involves the abnormal activation of NF‐αB and cAMP response element binding pathways. Importantly, using patient‐derived tumors and cell lines, we identified a correlation between the levels of PML expression and sumoylation and the sensitivity of tumors to anticancer treatments.—Swayden, M., Alzeeb, G., Masoud, R., Berthois, Y., Audebert, S., Camoin, L., Hannouche, L., Vachon, H., Gayet, O., Bigonnet, M., Roques, J., Silvy, F., Carrier, A., Dusetti, N., Iovanna, J. L., Soubeyran, P. PML hyposumoylation is responsible for the resistance of pancreatic cancer. FASEB J. 33, 12447–12463 (2019). www.fasebj.org