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

Content Provider	Springer Nature Link
Author	Ahn, Jeonghyun Woo, Ha Na Ko, Ara Khim, Maria Kim, Catherine Park, Nung Hwa Song, Ho Young Kim, Seong Who Lee, Heuiran
Copyright Year	2012
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 cross-species siRNA should greatly facilitate the development of siRNA-based therapeutic agents.
Starting Page	3147
Ending Page	3158
Page Count	12
File Format	PDF
ISSN	1420682X
Journal	Cellular and Molecular Life Sciences
Volume Number	69
Issue Number	18
e-ISSN	14209071
Language	English
Publisher	SP Birkhäuser Verlag Basel
Publisher Date	2012-05-05
Publisher Place	Basel
Access Restriction	Subscribed
Subject Keyword	Small-interfering RNA Cross-species activity Mammalian target of rapamycin CAPSID Tumor therapeutics Biomedicine general Life Sciences Cell Biology Biochemistry
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology Molecular Medicine Pharmacology Cellular and Molecular Neuroscience

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