Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors

Caterina Ierano, Arup R. Chakraborty, Alina Nicolae, Julian C. Bahr, Zhirong Zhan, Stefania Pittaluga, Susan E. Bates, Robert W. Robey

Research output: Contribution to journalArticle

Abstract

Burkitt lymphoma is characterized by deregulation of c-myc, and therapies targeting c-myc are under investigation as treatments. Histone deacetylase inhibitors are known to abrogate c-myc expression, leading us to examine their effect in a series of Burkitt lymphoma cell lines. While treatment with romidepsin, panobinostat, vorinostat, or belinostat for 48 h resulted in complete cell death in the Ramos and ST486 lines, CA46 and DG75 cells were resistant. In parallel studies, CA46 and DG75 cells were also insensitive to 48 h treatment with the Aurora kinase inhibitors (AKIs) MLN8237 (alisertib), VX-680 (tozasertib), or ZM447439. Bax knockdown is known to lead to HDI resistance, and we found that loss of Bax or both Bak and Bax correlated with resistance to both AKIs and HDIs in the Burkitt cell lines. As proof-of-concept to evaluate the contribution of Bax and Bak to HDI-mediated apoptosis, we found that apoptosis was unaffected in HCT-116 colon carcinoma cells lacking Bak, blunted in cells lacking Bax, and nearly completely abrogated in cells lacking both Bak and Bax compared with wild-type cells. To explore potential clinical variations in Bak and Bax expression, a series of samples from 16 patients diagnosed with Burkitt lymphoma was examined. While the majority of samples were positive for both Bak and Bax, some (3/16) expressed low levels of both proteins. We thus conclude that HDI-mediated and AKI-mediated apoptosis requires mitochondrial engagement, and that baseline Bax and Bak expression may serve as biomarkers for patients with Burkitt lymphoma likely to respond to HDI treatment.

Original languageEnglish
Pages (from-to)2829-2838
Number of pages10
JournalCell Cycle
Volume12
Issue number17
DOIs
Publication statusPublished - Sep 1 2013

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Keywords

  • Bak
  • Bax
  • Histone deacetylase inhibitor
  • Romidepsin
  • Vorinostat

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

Ierano, C., Chakraborty, A. R., Nicolae, A., Bahr, J. C., Zhan, Z., Pittaluga, S., Bates, S. E., & Robey, R. W. (2013). Loss of the proteins Bak and Bax prevents apoptosis mediated by histone deacetylase inhibitors. Cell Cycle, 12(17), 2829-2838. https://doi.org/10.4161/cc.25914