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EMBO Rep. 2018 Sep;19(9). pii: e45235. doi: 10.15252/embr.201745235. Epub 2018 Jul 9.

Phosphorylation switches Bax from promoting to inhibiting apoptosis thereby increasing drug resistance.

Author information

1
Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada.
2
Department of Medical Genetics, Adana Medical and Research Center, Baskent University School of Medicine, Adana, Turkey.
3
Faculdade de Ciências da Saúde, Universidade Federal da Grande Dourados, Dourados, Mato Grosso do Sul, Brazil.
4
Wellcome Trust Sanger Institute, Cambridge, UK.
5
Departments of Biochemistry and Biomedical Sciences, and Medicine, McMaster University, Hamilton, ON, Canada.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA anthony_letai@dfci.harvard.edu david.andrews@sri.utoronto.ca.
7
Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada anthony_letai@dfci.harvard.edu david.andrews@sri.utoronto.ca.
8
Departments of Biochemistry and Medical Biophysics, University of Toronto, Toronto, ON, Canada.

Abstract

Akt is a pro-survival kinase frequently activated in human cancers and is associated with more aggressive tumors that resist therapy. Here, we connect Akt pathway activation to reduced sensitivity to chemotherapy via Akt phosphorylation of Bax at residue S184, one of the pro-apoptotic Bcl-2 family proteins required for cells to undergo apoptosis. We show that phosphorylation by Akt converts the pro-apoptotic protein Bax into an anti-apoptotic protein. Mechanistically, we show that phosphorylation (i) enables Bax binding to pro-apoptotic BH3 proteins in solution, and (ii) prevents Bax inserting into mitochondria. Together, these alterations promote resistance to apoptotic stimuli by sequestering pro-apoptotic activator BH3 proteins. Bax phosphorylation correlates with cellular resistance to BH3 mimetics in primary ovarian cancer cells. Further, analysis of the TCGA database reveals that 98% of cancer patients with increased BAX levels also have an upregulated Akt pathway, compared to 47% of patients with unchanged or decreased BAX levels. These results suggest that in patients, increased phosphorylated anti-apoptotic Bax promotes resistance of cancer cells to inherent and drug-induced apoptosis.

KEYWORDS:

Akt; Bax; Bcl‐2 family proteins; cancer; drug resistance

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