{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Karpel-Massler G"],"funding":["NCATS NIH HHS","NINDS NIH HHS"],"pagination":["1067"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC5651864"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["8(1)"],"pubmed_abstract":["Certain gliomas often harbor a mutation in the activity center of IDH1 (R132H), which leads to the production of the oncometabolite 2-R-2-hydroxyglutarate (2-HG). In six model systems, including patient-derived stem cell-like glioblastoma cultures, inhibition of Bcl-xL induces significantly more apoptosis in IDH1-mutated cells than in wild-type IDH1 cells. Anaplastic astrocytoma samples with mutated IDH1 display lower levels of Mcl-1 than IDH1 wild-type tumors and specific knockdown of Mcl-1 broadly sensitizes glioblastoma cells to Bcl-xL inhibition-mediated apoptosis. Addition of 2-HG to glioblastoma cultures recapitulates the effects of the IDH mutation on intrinsic apoptosis, shuts down oxidative phosphorylation and reduces ATP levels in glioblastoma cells. 2-HG-mediated energy depletion activates AMPK (Threonine 172), blunting protein synthesis and mTOR signaling, culminating in a decline of Mcl-1. In an orthotopic glioblastoma xenograft model expressing mutated IDH1, Bcl-xL inhibition leads to long-term survival. These results demonstrate that IDH1-mutated gliomas are particularly vulnerable to Bcl-xL inhibition."],"journal":["Nature communications"],"pubmed_title":["Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL."],"pmcid":["PMC5651864"],"funding_grant_id":["R01 NS073610","UL1 TR001430","R01 NS095848","K08 NS083732"],"pubmed_authors":["Canoll P","Shu C","Bruce JN","Ishida CT","Garcia F","Bianchetti E","Zhang Y","Karpel-Massler G","Siegelin MD","Banu MA","Tsujiuchi T","Roth KA"],"additional_accession":[]},"is_claimable":false,"name":"Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL.","description":"Certain gliomas often harbor a mutation in the activity center of IDH1 (R132H), which leads to the production of the oncometabolite 2-R-2-hydroxyglutarate (2-HG). In six model systems, including patient-derived stem cell-like glioblastoma cultures, inhibition of Bcl-xL induces significantly more apoptosis in IDH1-mutated cells than in wild-type IDH1 cells. Anaplastic astrocytoma samples with mutated IDH1 display lower levels of Mcl-1 than IDH1 wild-type tumors and specific knockdown of Mcl-1 broadly sensitizes glioblastoma cells to Bcl-xL inhibition-mediated apoptosis. Addition of 2-HG to glioblastoma cultures recapitulates the effects of the IDH mutation on intrinsic apoptosis, shuts down oxidative phosphorylation and reduces ATP levels in glioblastoma cells. 2-HG-mediated energy depletion activates AMPK (Threonine 172), blunting protein synthesis and mTOR signaling, culminating in a decline of Mcl-1. In an orthotopic glioblastoma xenograft model expressing mutated IDH1, Bcl-xL inhibition leads to long-term survival. These results demonstrate that IDH1-mutated gliomas are particularly vulnerable to Bcl-xL inhibition.","dates":{"release":"2017-01-01T00:00:00Z","publication":"2017 Oct","modification":"2025-04-20T03:40:31.342Z","creation":"2019-03-27T02:59:37Z"},"accession":"S-EPMC5651864","cross_references":{"pubmed":["29057925"],"doi":["10.1038/s41467-017-00984-9"]}}