Multispecies-compatible antitumor effects of a cross-species small-interfering RNA against mammalian target of rapamycin

Jeonghyun Ahn, Ha Na Woo, Ara Ko, Maria Khim, Catherine Kim, Nung Hwa Park, Ho Young Song, Seong Who Kim, Heuiran Lee

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Successful development of sequence-specific siRNA (small interfering RNA)-based drugs requires an siRNA design that functions consistently in different organisms. Utilizing the CAPSID program previously developed by our group, we here designed siRNAs against mammalian target of rapamycin (mTOR) that are entirely complementary among various species and investigated their multispecies-compatible gene-silencing properties. The mTOR siRNAs markedly reduced mTOR expression at both the mRNA and protein levels in human, mouse, and monkey cell lines. The reduction in mTOR expression resulted in inactivation of both mTOR complex I and II signaling pathways, as confirmed by reduced phosphorylation of p70S6K (70-kDa ribosomal protein S6 kinase), 4EBP1 (eIF4E-binding protein 1), and AKT, and nuclear accumulation of FOXO1 (forkhead box O1), with consequent cell-cycle arrest, proliferation inhibition, and autophagy activation. Moreover, interfering with mTOR activity in vivo using mTOR small-hairpin RNA-expressing recombinant adeno-associated virus led to significant antitumor effects in xenograft and allograft models. Thus, the present study demonstrates that cross-species siRNA successfully silences its target and readily produces multispecies- compatible phenotypic alterations-antitumor effects in the case of mTOR siRNA. Application of crossspecies siRNA should greatly facilitate the development of siRNA-based therapeutic agents.

Original languageEnglish (US)
Pages (from-to)3147-3158
Number of pages12
JournalCellular and Molecular Life Sciences
Volume69
Issue number18
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

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Keywords

  • CAPSID
  • Cross-species activity
  • Mammalian target of rapamycin
  • Small-interfering RNA
  • Tumor therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology

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