Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/32687
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dc.contributor.authorBusacca, Sara-
dc.contributor.authorChacko, A. D.-
dc.contributor.authorKlabatsa, A.-
dc.contributor.authorArthur, K.-
dc.contributor.authorSheaff, M.-
dc.contributor.authorBarbone, D.-
dc.contributor.authorMutti, L.-
dc.contributor.authorGunasekharan, V. K.-
dc.contributor.authorGorski, J. J.-
dc.contributor.authorEl-Tanani, M.-
dc.contributor.authorBroaddus, V. C.-
dc.contributor.authorGaudino, G.-
dc.contributor.authorFennell, Dean A.-
dc.date.accessioned2015-07-14T14:01:30Z-
dc.date.available2015-07-14T14:01:30Z-
dc.date.issued2013-06-07-
dc.identifier.citationPLoS One, 2013, 8 (6), e65489en
dc.identifier.urihttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065489en
dc.identifier.urihttp://hdl.handle.net/2381/32687-
dc.description.abstractBased on promising preclinical efficacy associated with the 20S proteasome inhibitor bortezomib in malignant pleural mesothelioma (MPM), two phase II clinical trials have been initiated (EORTC 08052 and ICORG 05-10). However, the potential mechanisms underlying resistance to this targeted drug in MPM are still unknown. Functional genetic analyses were conducted to determine the key mitochondrial apoptotic regulators required for bortezomib sensitivity and to establish how their dysregulation may confer resistance. The multidomain proapoptotic protein BAK, but not its orthologue BAX, was found to be essential for bortezomib-induced apoptosis in MPM cell lines. Immunohistochemistry was performed on tissues from the ICORG-05 phase II trial and a TMA of archived mesotheliomas. Loss of BAK was found in 39% of specimens and loss of both BAX/BAK in 37% of samples. However, MPM tissues from patients who failed to respond to bortezomib and MPM cell lines selected for resistance to bortezomib conserved BAK expression. In contrast, c-Myc dependent transactivation of NOXA was abrogated in the resistant cell lines. In summary, the block of mitochondrial apoptosis is a limiting factor for achieving efficacy of bortezomib in MPM, and the observed loss of BAK expression or NOXA transactivation may be relevant mechanisms of resistance in the clinic.en
dc.language.isoenen
dc.publisherPublic Library of Scienceen
dc.relation.urihttp://www.ncbi.nlm.nih.gov/pubmed/23762382-
dc.rightsCopyright © 2013 Busacca et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subjectAnimalsen
dc.subjectApoptosisen
dc.subjectBoronic Acidsen
dc.subjectCell Line, Tumoren
dc.subjectDown-Regulationen
dc.subjectDrug Resistance, Neoplasmen
dc.subjectEmbryo, Mammalianen
dc.subjectFibroblastsen
dc.subjectGene Expression Regulation, Neoplasticen
dc.subjectImmunohistochemistryen
dc.subjectMesotheliomaen
dc.subjectMiceen
dc.subjectMitochondriaen
dc.subjectProto-Oncogene Proteins c-bcl-2en
dc.subjectProto-Oncogene Proteins c-mycen
dc.subjectPyrazinesen
dc.subjectTranscription, Geneticen
dc.subjectbcl-2 Homologous Antagonist-Killer Proteinen
dc.subjectbcl-2-Associated X Proteinen
dc.titleBAK and NOXA are critical determinants of mitochondrial apoptosis induced by bortezomib in mesothelioma.en
dc.typeJournal Articleen
dc.identifier.doi10.1371/journal.pone.0065489-
dc.identifier.eissn1932-6203-
dc.identifier.piiPONE-D-12-34046-
dc.description.statusPeer-revieweden
dc.description.versionPublisher Versionen
dc.type.subtypeJournal Article;Research Support, N.I.H., Extramural;Research Support, Non-U.S. Gov't-
pubs.organisational-group/Organisationen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGYen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicineen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicineen
dc.dateaccepted2013-04-25-
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

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