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

• Published in: EMBO reports Vol. 19; no. 9
• Main Authors: Kale, Justin, Kutuk, Ozgur, Brito, Glauber Costa, Andrews, Tallulah S, Leber, Brian, Letai, Anthony, Andrews, David W
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2018; Blackwell Publishing Ltd; John Wiley and Sons Inc
• Subjects: Akt; AKT protein; Apoptosis; Bax; BAX protein; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Bcl‐2 family proteins; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cancer; Cell Membrane Permeability; Cells, Cultured; Chemotherapy; Correlation; Drug resistance; Drug Resistance, Neoplasm; EMBO03; EMBO07; EMBO37; Female; Humans; Kinases; MCF-7 Cells; Mitochondria; Mitochondria - metabolism; Mutation; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Patients; Peptide Fragments - metabolism; Phosphorylation; Protein Binding; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Sequestering; Signal transduction; Switches; Tumor cell lines; Tumors; Bax; Bcl‐2 family proteins; cancer; Akt; drug resistance
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.201745235

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. Synopsis Phosphorylation of Bax at S184 by Akt converts it from pro‐ to anti‐apoptotic and confers resistance to drugs and pro‐apoptotic signalling. In patients, Akt is increased in tumours with high Bax and phosphorylation correlates with drug resistance. Phosphorylation of Bax at residue S184 by Akt inhibits apoptosis in cancer cell lines. Phosphorylation converts pro‐apoptotic Bax into an anti‐apoptotic protein. Phosphomimetic Bax sequesters and thereby inactivates pro‐apoptotic BH3‐proteins. In patients, levels of Akt and Bax are correlated and Bax phosphorylation correlates with resistance to BH3‐mimetics. Graphical Abstract Phosphorylation of Bax at S184 by Akt converts it from pro‐ to anti‐apoptotic and confers resistance to drugs and pro‐apoptotic signalling. In patients, Akt is increased in tumours with high Bax and phosphorylation correlates with drug resistance.