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Publication

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

eLife | 2017

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.

Pubmed ID: 29063830 RIS Download

Research resources used in this publication

Additional research tools detected in this publication

Antibodies used in this publication

Associated grants

Agency: NCI NIH HHS, United States
Id: R35 CA197450
Agency: NCI NIH HHS, United States
Id: R50 CA211271
Agency: NCI NIH HHS, United States
Id: T32 CA009560
Agency: NCI NIH HHS, United States
Id: T32 CA070085

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This is a list of tools and resources that we have found mentioned in this publication.

ATCC (tool)

RRID:SCR_001672

Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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Bio-Rad Laboratories (tool)

RRID:SCR_008426

Commercial instrument and chemical vendor. Developer and manufacturer of specialized technological products for life science research and clinical diagnostics markets.

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QIAGEN (tool)

RRID:SCR_008539

A commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.

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Ensembl (tool)

RRID:SCR_002344

Collection of genome databases for vertebrates and other eukaryotic species with DNA and protein sequence search capabilities. Used to automatically annotate genome, integrate this annotation with other available biological data and make data publicly available via web. Ensembl tools include BLAST, BLAT, BioMart and the Variant Effect Predictor (VEP) for all supported species.

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Phoenix (tool)

RRID:SCR_003163

A second-generation retrovirus producer lines for the generation of helper free ecotropic and amphotropic retroviruses. The lines are based on the 293T cell line (a human embryonic kidney line transformed with adenovirus E1a and carrying a temperature sensitive T antigen co-selected with neomycin). The unique feature of this cell line is that it is highly transfectable with either calcium phosphate mediated transfection or lipid-based transfection protocols-- up to 50% or higher of cells can be transiently transfected. The lines were created by placing into 293T cells constructs capable of producing gag-pol, and envelope protein for ecotropic and amphotropic viruses. The lines offered advantages over previous stable systems in that virus can be produced in just a few days. Academic and non-profit laboratories may obtain the Phoenix cells from either Allele Biotechnology or the National Gene Vector Bank. The vectors may be obtained from Addgene. They are no longer distributing these reagents from the lab.

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Gene Set Enrichment Analysis (tool)

RRID:SCR_003199

Software package for interpreting gene expression data. Used for interpretation of a large-scale experiment by identifying pathways and processes.

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HTSeq (tool)

RRID:SCR_005514

THIS RESOURCE IS NO LONGER IN SERVICE. Documented on February 28,2023. Software Python package that provides infrastructure to process data from high-throughput sequencing assays. While the main purpose of HTSeq is to allow you to write your own analysis scripts, customized to your needs, there are also a couple of stand-alone scripts for common tasks that can be used without any Python knowledge.

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Bioconductor (tool)

RRID:SCR_006442

Software repository for R packages related to analysis and comprehension of high throughput genomic data. Uses separate set of commands for installation of packages. Software project based on R programming language that provides tools for analysis and comprehension of high throughput genomic data.

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edgeR (tool)

RRID:SCR_012802

Bioconductor software package for Empirical analysis of Digital Gene Expression data in R. Used for differential expression analysis of RNA-seq and digital gene expression data with biological replication.

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DESeq2 (tool)

RRID:SCR_015687

Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.

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BD FACSAria II Cell Sorter (tool)

RRID:SCR_018934

Cell sorter features hardware and software enhancements that improve overall ease of use, flexibility,and aseptic capability. Offers new options in lasers and nozzles to support more advanced multicolor applications. Built on fixed alignment technology. FACSAria II cell sorter is first generation of BD FACSAria system where flow cell is in true fixed alignment with laser, to reduce startup time and improve reproducibility.

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HEK293 (tool)

RRID:CVCL_0045

Cell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)

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Mouse Anti-CD95 Monoclonal Antibody, FITC Conjugated, Clone DX2 (antibody)

RRID:AB_396506

This monoclonal targets CD95

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RRID:AB_2687483

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Mouse IgG1, kappa Isotype Control, FITC Conjugated, Clone MOPC-21 (antibody)

RRID:AB_394297

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Recombinant Anti-Argonaute-2 antibody [EPR10411] (antibody)

RRID:AB_2713978

This recombinant monoclonal targets Argonaute-2

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Goat Anti-Mouse IgG1, Human ads-HRP (antibody)

RRID:AB_2650509

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Drosha (D28B1) Rabbit mAb (antibody)

RRID:AB_2238644

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Anti-β-Actin Antibody (C4) (antibody)

RRID:AB_626632

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Anti-rabbit IgG, HRP-linked Antibody (antibody)

RRID:AB_2099233

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Rabbit Anti-Human FAS (C-20) Polyclonal, Unconjugated (antibody)

RRID:AB_2100386

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Dicer Antibody (antibody)

RRID:AB_2093073

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Mouse Anti-CD178 Monoclonal Antibody, Unconjugated, Clone G247-4 (antibody)

RRID:AB_396402

This monoclonal targets CD178

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RStudio (software resource)

RRID:SCR_000432

Open source and enterprise ready professional software for R statistical computing environment. Integrated development environment for R. Includes console, syntax highlighting editor that supports direct code execution, as well as tools for plotting, history, debugging and workspace management. Available in open source and commercial editions and runs on desktop Windows, Mac, and Linux or in browser connected to RStudio Server or RStudio Server Pro (Debian/Ubuntu, RedHat/CentOS, and SUSE Linux).

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