Document Detail


Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells.
MedLine Citation:
PMID:  18355723     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We screened small molecules to identify two compounds, which we named RSL3 and RSL5, that have increased lethality in the presence of oncogenic RAS. Counter screening with biologically active compounds defined aspects of the mechanism of action for RSL3 and RSL5, such as a nonapoptotic, MEK-dependent, and iron-dependent oxidative cell death. Erastin, a previously reported compound with RAS-selective lethality, showed similar properties. RNA interference experiments targeting voltage-dependent anion channel 3 (VDAC3), a target of erastin, demonstrated that RSL5 is a scaffold that acts through VDACs to activate the observed pathway. RSL3 activated a similar death mechanism but in a VDAC-independent manner. We found that cells transformed with oncogenic RAS have increased iron content relative to their normal cell counterparts through upregulation of transferrin receptor 1 and downregulation of ferritin heavy chain 1 and ferritin light chain.
Authors:
Wan Seok Yang; Brent R Stockwell
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemistry & biology     Volume:  15     ISSN:  1074-5521     ISO Abbreviation:  Chem. Biol.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-21     Completed Date:  2008-05-23     Revised Date:  2011-08-01    
Medline Journal Info:
Nlm Unique ID:  9500160     Medline TA:  Chem Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  234-45     Citation Subset:  IM    
Affiliation:
Department of Biological Sciences, Columbia University, Fairchild Center, MC2406, 1212 Amsterdam Avenue, New York, NY 10027, USA.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis
Cell Death / drug effects
Cell Line, Tumor
Drug Evaluation, Preclinical
Gene Expression Regulation, Neoplastic / drug effects
Humans
Iron / metabolism*
Mutation
Neoplasms / drug therapy,  metabolism*,  pathology*
Piperazines / pharmacology
Proto-Oncogene Proteins p21(ras) / genetics*,  metabolism*
Small Molecule Libraries / pharmacology*
Substrate Specificity
Voltage-Dependent Anion Channels / metabolism
Grant Support
ID/Acronym/Agency:
R01 CA097061-01/CA/NCI NIH HHS; R01 CA097061-02/CA/NCI NIH HHS; R01 CA097061-03/CA/NCI NIH HHS; R01 CA097061-04/CA/NCI NIH HHS; R01 CA097061-05A1/CA/NCI NIH HHS; R01 CA097061-06/CA/NCI NIH HHS; R01CA097061/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Piperazines; 0/Small Molecule Libraries; 0/Voltage-Dependent Anion Channels; 0/erastin; 7439-89-6/Iron; EC 3.6.5.2/Proto-Oncogene Proteins p21(ras)
Comments/Corrections

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