Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism

Over 80% of multiple-tested siRNAs and shRNAs targeting CD95 or CD95 ligand (CD95L) induce a form of cell death characterized by simultaneous activation of multiple cell death pathways preferentially killing transformed and cancer stem cells. We now show these si/shRNAs kill cancer cells through can...

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Bibliographic Details
Published in:eLife 2017-10, Vol.6
Main Authors: Putzbach, William, Gao, Quan Q, Patel, Monal, van Dongen, Stijn, Haluck-Kangas, Ashley, Sarshad, Aishe A, Bartom, Elizabeth T, Kim, Kwang-Youn A, Scholtens, Denise M, Hafner, Markus, Zhao, Jonathan C, Murmann, Andrea E, Peter, Marcus E
Format: Article
Language:English
Subjects:
3' Untranslated regions
antagonists & inhibitors
Antineoplastic Agents
Antineoplastic Agents - metabolism
Apoptosis
Basic Medicine
Cancer
Cancer Biology
CD95 antigen
Cell activation
Cell Biology
Cell Death
Cell growth
Cell Line
Cell Line, Tumor
Cell Survival
DISE
Fas
Fas Ligand Protein
Fas Ligand Protein - antagonists & inhibitors
fas Receptor
fas Receptor - antagonists & inhibitors
FasL protein
Gene expression
Genomes
Humans
Medical research
Medicinska grundvetenskaper
metabolism
mRNA
RNA
RNA Interference
RNA, Small Interfering - metabolism
RNA-mediated interference
RNAi
siRNA
Small Interfering
Stem cells
Tumor
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Summary:Over 80% of multiple-tested siRNAs and shRNAs targeting CD95 or CD95 ligand (CD95L) induce a form of cell death characterized by simultaneous activation of multiple cell death pathways preferentially killing transformed and cancer stem cells. We now show these si/shRNAs kill cancer cells through canonical RNAi by targeting the 3'UTR of critical survival genes in a unique form of off-target effect we call DISE (death induced by survival gene elimination). Drosha and Dicer-deficient cells, devoid of most miRNAs, are hypersensitive to DISE, suggesting cellular miRNAs protect cells from this form of cell death. By testing 4666 shRNAs derived from the CD95 and CD95L mRNA sequences and an unrelated control gene, Venus, we have identified many toxic sequences - most of them located in the open reading frame of CD95L. We propose that specific toxic RNAi-active sequences present in the genome can kill cancer cells.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.29702