Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, United States
Stijn van Dongen
European Bioinformatics Institute (EMBL-EBI), Cambridge, United Kingdom
Ashley Haluck-Kangas
Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, United States
Aishe A Sarshad
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States
Elizabeth T Bartom
Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, United States
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, United States
Jonathan C Zhao
Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, United States
Andrea E Murmann
Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, United States
Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, United States; Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, United States
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.
