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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  BH 3 proteins in solution, and (ii) prevents Bax inserting into mitochondria. Together, these alterations promote resistance to apoptotic stimuli by sequestering pro‐apoptotic activator  BH 3 proteins. Bax phosphorylation correlates with cellular resistance to  BH 3 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.

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