Phosphorylation switches Bax from promoting to inhibiting apoptosis thereby increasing drug resistance. (10th July 2018)

• Record Type: Journal Article
• Authors: Kale, Justin; Kutuk, Ozgur; Brito, Glauber Costa; Andrews, Tallulah S; Leber, Brian; Letai, Anthony; Andrews, David W
• Is Part Of: EMBO reports. Volume 19:Number 9(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-07-10
• Subjects: Akt -- Bax -- Bcl‐2 family proteins -- cancer -- drug resistance; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201745235
• Languages: English
• ISSNs: 1469-221X

Abstract

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. 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. 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.