Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29063830.
- Also identified by DOI 10.7554/eLife.29702 and PMC identifier 5655136.
- Licence recorded as CC0.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
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.
Medical subject headings
- Antineoplastic Agents
- Cell Death
- Fas Ligand Protein
- RNA, Small Interfering
- fas Receptor