Abstract:
:Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease.
journal_name
Proc Natl Acad Sci U S Aauthors
Lucki NC,Villa GR,Vergani N,Bollong MJ,Beyer BA,Lee JW,Anglin JL,Spangenberg SH,Chin EN,Sharma A,Johnson K,Sander PN,Gordon P,Skirboll SL,Wurdak H,Schultz PG,Mischel PS,Lairson LLdoi
10.1073/pnas.1816626116subject
Has Abstractpub_date
2019-03-26 00:00:00pages
6435-6440issue
13eissn
0027-8424issn
1091-6490pii
1816626116journal_volume
116pub_type
杂志文章abstract::Many bacteria use acyl homoserine lactone signals to monitor cell density in a type of gene regulation termed quorum sensing and response. Synthesis of these signals is directed by homologs of the luxi gene of Vibrio fischeri. This communication resolves two critical issues concerning the synthesis of the V. fischeri ...
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