The Bcl-2 repertoire of mesothelioma spheroids underlies acquired apoptotic multicellular resistance

D. Barbone, J. A. Ryan, N. Kolhatkar, A. D. Chacko, D. M. Jablons, D. J. Sugarbaker, R. Bueno, A. G. Letai, L. M. Coussens, D. A. Fennell, V. C. Broaddus

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Three-dimensional (3D) cultures are a valuable platform to study acquired multicellular apoptotic resistance of cancer. We used spheroids of cell lines and actual tumor to study resistance to the proteasome inhibitor bortezomib in mesothelioma, a highly chemoresistant tumor. Spheroids from mesothelioma cell lines acquired resistance to bortezomib by failing to upregulate Noxa, a pro-apoptotic sensitizer BH3-only protein that acts by displacing Bim, a pro-apoptotic Bax/Bak-activator protein. Surprisingly, despite their resistance, spheroids also upregulated Bim and thereby acquired sensitivity to ABT-737, an inhibitor of antiapoptotic Bcl-2 molecules. Analysis using BH3 profiling confirmed that spheroids acquired a dependence on anti-apoptotic Bcl-2 proteins and were 'primed for death'. We then studied spheroids grown from actual mesothelioma. ABT-737 was active in spheroids grown from those tumors (5/7,∼70%) with elevated levels of Bim. Using immunocytochemistry of tissue microarrays of 48 mesotheliomas, we found that most (33, 69%) expressed elevated Bim. In conclusion, mesothelioma cells in 3D alter the expression of Bcl-2 molecules, thereby acquiring both apoptotic resistance and sensitivity to Bcl-2 blockade. Mesothelioma tumors ex vivo also show sensitivity to Bcl-2 blockade that may depend on Bim, which is frequently elevated in mesothelioma. Therefore, mesothelioma, a highly resistant tumor, may have an intrinsic sensitivity to Bcl-2 blockade that can be exploited therapeutically.

Original languageEnglish (US)
Article numbere174
JournalCell Death and Disease
Volume2
Issue number6
DOIs
StatePublished - Jun 2011

Keywords

  • 3D
  • BH3-profiling
  • Bortezomib
  • Chemotherapy
  • Mitochondria

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    Barbone, D., Ryan, J. A., Kolhatkar, N., Chacko, A. D., Jablons, D. M., Sugarbaker, D. J., Bueno, R., Letai, A. G., Coussens, L. M., Fennell, D. A., & Broaddus, V. C. (2011). The Bcl-2 repertoire of mesothelioma spheroids underlies acquired apoptotic multicellular resistance. Cell Death and Disease, 2(6), [e174]. https://doi.org/10.1038/cddis.2011.58