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BAK and NOXA are critical determinants of mitochondrial apoptosis induced by bortezomib in mesothelioma.

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journal contribution
posted on 2015-07-14, 14:01 authored by Sara Busacca, A. D. Chacko, A. Klabatsa, K. Arthur, M. Sheaff, D. Barbone, L. Mutti, V. K. Gunasekharan, J. J. Gorski, M. El-Tanani, V. C. Broaddus, G. Gaudino, Dean A. Fennell
Based 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.

History

Citation

PLoS One, 2013, 8 (6), e65489

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine

Version

  • VoR (Version of Record)

Published in

PLoS One

Publisher

Public Library of Science

eissn

1932-6203

Acceptance date

2013-04-25

Copyright date

2013

Available date

2015-07-14

Publisher version

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0065489

Language

en