JNK and macroautophagy activation by bortezomib has a pro-survival effect in primary effusion lymphoma cells

Understanding the mechanisms of autophagy induction and its role during chemotherapeutic treatments is of fundamental importance in order to manipulate it to improve the outcome of chemotherapy. In particular whether the bortezomib-induced autophagy plays a pro-survival or pro-death role is still co...

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Bibliographic Details
Published in:PloS one 2013-09, Vol.8 (9), p.e75965-e75965
Main Authors: Granato, Marisa, Santarelli, Roberta, Lotti, Lavinia V, Di Renzo, Livia, Gonnella, Roberta, Garufi, Alessia, Trivedi, Pankaj, Frati, Luigi, D'Orazi, Gabriella, Faggioni, Alberto, Cirone, Mara
Format: Article
Language:English
Subjects:
Activation
Apoptosis
Autophagy
Autophagy - drug effects
B-cell lymphoma
Bcl-2 protein
Blotting, Western
Boronic Acids - pharmacology
Bortezomib
Cancer therapies
Cell death
Cell survival
Chemotherapy
Cytotoxicity
Effusion
Endoplasmic reticulum
Endoplasmic Reticulum Stress - drug effects
Endoplasmic Reticulum Stress - physiology
Enzyme Activation - drug effects
Gene expression
Gene Knockdown Techniques
Humans
JNK protein
Kinases
Laboratories
Lung cancer
Lymphocytes B
Lymphoma
Lymphoma, Primary Effusion - enzymology
Lymphoma, Primary Effusion - immunology
MAP Kinase Kinase 4 - metabolism
Medical prognosis
Medicine
Microscopy, Electron
Multiple myeloma
Phagocytosis
Phosphorylation
Poly(ADP-ribose) polymerase
Primary effusion lymphoma
Proteins
Proto-Oncogene Proteins c-bcl-2 - metabolism
Pyrazines - pharmacology
Reverse Transcriptase Polymerase Chain Reaction
Rodents
Survival
Transcription factors
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Summary:Understanding the mechanisms of autophagy induction and its role during chemotherapeutic treatments is of fundamental importance in order to manipulate it to improve the outcome of chemotherapy. In particular whether the bortezomib-induced autophagy plays a pro-survival or pro-death role is still controversial. In this study we investigated if bortezomib induced endoplasmic reticulum (ER) stress and activated autophagy in Primary Effusion Lymphoma (PEL) cells and how they influenced cell survival. We found that bortezomib induced up-regulation of the pro-survival and pro-death ER stress molecules BIP and CHOP and activated c-Jun NH2-terminal kinase (JNK), resulting in Bcl-2 phosphorylation and induction of autophagy. JNK and autophagy activation played a pro-survival role in this setting, thus their inhibition increased the bortezomib cytotoxic effect and PARP cleavage in PEL cells. Based on our results we suggest that the combination of bortezomib with JNK or autophagy inhibitors could be exploited to improve the outcome of therapy of this aggressive B cell lymphoma.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0075965