Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells.
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.
Yang
Wan Seok
WS
Department of Biological Sciences, Columbia University, Fairchild Center, MC2406, 1212 Amsterdam Avenue, New York, NY 10027, USA.
Stockwell
Brent R
BR
D017209:Apoptosis; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism*; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013379:Substrate Specificity; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
D010879:Piperazines; D054852:Small Molecule Libraries; D050994:Voltage-Dependent Anion Channels; C477224:erastin; D007501:Iron; D016283:Proto-Oncogene Proteins p21(ras)