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

dc.contributor.authorKutuk, Ozgur
dc.contributor.authorKale, Justin
dc.contributor.authorBrito, Glauber Costa
dc.contributor.authorAndrews, Talluhan S.
dc.contributor.authorLeber, Brian
dc.contributor.authorLetai, Anthony
dc.contributor.authorAndrews, David W.
dc.contributor.orcID0000-0001-9854-7220en_US
dc.contributor.researcherIDAAH-1671-2019en_US
dc.date.accessioned2019-05-05T09:09:35Z
dc.date.available2019-05-05T09:09:35Z
dc.date.issued2018
dc.description.abstractAkt 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.en_US
dc.identifier.issn1469-221X
dc.identifier.issue9en_US
dc.identifier.scopus2-s2.0-85050401832en_US
dc.identifier.scopus29987135en_US
dc.identifier.urihttp://embor.embopress.org/content/embor/19/9/e45235.full.pdf
dc.identifier.urihttp://hdl.handle.net/11727/3152
dc.identifier.volume19en_US
dc.identifier.wos000443682200003en_US
dc.language.isoengen_US
dc.relation.isversionof10.15252/embr.201745235en_US
dc.relation.journalEMBO REPORTSen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergien_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectAkten_US
dc.subjectBaxen_US
dc.subjectBcl-2 family proteinsen_US
dc.subjectCanceren_US
dc.subjectDrug resistanceen_US
dc.titlePhosphorylation switches Bax from promoting to inhibiting apoptosis thereby increasing drug resistanceen_US
dc.typearticleen_US

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