Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

Andrea E. Murmann*, Quan Q. Gao, William Putzbach, Monal Patel, Elizabeth T. Bartom, Calvin Law, Bryan Bridgeman, Siquan Chen, Kaylin M. McMahon, C. Shad Thaxton, Marcus E. Peter

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Trinucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington’s disease (HD). Pathology is caused by protein and RNA generated from the TNR regions including small siRNA-sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients. We now show that siRNAs based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complimentary TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the 6 members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells. siCAG/CUG TNR-based siRNAs induce cell death in vitro in all tested cancer cell lines and slow down tumor growth in a preclinical mouse model of ovarian cancer with no signs of toxicity to the mice. We propose to explore TNR-based siRNAs as a novel form of anti-cancer reagents.

Original languageEnglish (US)
JournalUnknown Journal
DOIs
StatePublished - Jan 12 2018

Keywords

  • CAG repeats
  • cell death
  • DISE
  • ovarian cancer
  • RNAi
  • TLP nanoparticles
  • TNR
  • trinucleotide repeats

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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