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

William Putzbach1, Quan Q Gao1, Monal Patel1

  • 1Division of Hematology and Oncology, Department of Medicine, Northwestern University, Chicago, United States.

Elife
|October 25, 2017
PubMed

Insights

RNA interference (RNAi) using siRNAs and shRNAs targeting CD95/CD95L can trigger a unique cell death mechanism, DISE, by eliminating survival genes. Cellular miRNAs appear to protect cells from this potent cancer cell-killing effect.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • RNA Interference

Background:

  • siRNAs and shRNAs targeting CD95/CD95L induce cell death in cancer cells.
  • This cell death preferentially affects transformed and cancer stem cells.
  • The mechanism involves simultaneous activation of multiple cell death pathways.

Purpose of the Study:

  • To elucidate the mechanism by which siRNAs/shRNAs targeting CD95/CD95L induce cancer cell death.
  • To identify the specific RNA sequences responsible for this effect.
  • To investigate the role of cellular miRNAs in this process.

Main Methods:

  • Testing 4666 shRNAs derived from CD95, CD95L, and Venus mRNA sequences.
  • Utilizing Drosha and Dicer-deficient cells to assess miRNA-dependent effects.
  • Analyzing off-target effects of RNA interference.

Main Results:

  • siRNAs/shRNAs kill cancer cells via canonical RNAi targeting 3'UTRs of survival genes, termed DISE (death induced by survival gene elimination).
  • Drosha and Dicer-deficient cells are hypersensitive to DISE, indicating a protective role for cellular miRNAs.
  • Toxic RNAi-active sequences, particularly in the CD95L open reading frame, were identified as potent cancer cell killers.

Conclusions:

  • DISE represents a novel form of RNAi-mediated cell death triggered by targeting survival genes.
  • Cellular miRNAs play a protective role against DISE.
  • Genomic RNAi-active sequences hold potential for cancer therapy by selectively eliminating cancer cells.
Keywords:
DISEFasRNAicancercancer biologycell biologyhuman

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