PT  - JOURNAL ARTICLE
AU  - William Putzbach
AU  - Quan Q. Gao
AU  - Monal Patel
AU  - Abbas Hadji
AU  - Stijn van Dongen
AU  - Ashley Haluck-Kangas
AU  - Elizabeth Bartom
AU  - Austin Stults
AU  - Abdul S. Qadir
AU  - Kwang-Youn A. Kim
AU  - Markus Hafner
AU  - Jonathan C. Zhao
AU  - Andrea E. Murmann
AU  - Marcus E. Peter
TI  - CD95L mRNA and CD95L derived si- and shRNAs kill cancer cells through an RNAi mechanism by targeting survival genes
AID  - 10.1101/141952
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 141952
4099  - http://biorxiv.org/content/early/2017/05/24/141952.short
4100  - http://biorxiv.org/content/early/2017/05/24/141952.full
AB  - Immune cells kill tumour cells by activating the CD95/Fas death receptor triggering apoptosis. Unexpectedly however, >80% of a large number of siRNAs and shRNAs tested targeting CD95 or CD95 ligand (CD95L) induce a robust form of cell death that is characterized by the simultaneous activation of multiple death pathways and preferentially affects transformed and cancer stem cells. We now show that si/shRNAs derived from CD95 or CD95L are toxic to cancer cells through canonical RNAi by targeting the 3’UTR of critical survival genes in a unique form of off-target effect. By testing 4666 shRNAs derived from the CD95 and CD95L mRNAs and an unrelated control gene, Venus, we have located the most toxic sequences in the open reading frame of CD95L. Consistently, CD95L mRNA is highly toxic to cancer cells after complete deletion of CD95. Our data provide the first evidence for mRNAs to affect cell fate through RNAi in mammalian cells. In addition, they suggest that cancer cells can be targeted with specific toxic RNAi active sequences present in the genome.