Reprogramming of the MicroRNA transcriptome mediates resistance to rapamycin

Hana Totary-Jain, Despina Sanoudou, Iddo Z. Ben-Dov, Cula N. Dautriche, Paolo Guarnieri, Steven O. Marx, Thomas Tuschl, Andrew R. Marks

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33 Citations (Scopus)

Abstract

The mammalian target of rapamycin (mTOR) is a central regulator of cell proliferation that is often deregulated in cancer. Inhibitors of mTOR, including rapamycin and its analogues, are being evaluated as antitumor agents. For their promise to be fulfilled, it is of paramount importance to identify the mechanisms of resistance and develop novel therapies to overcome it. Given the emerging role of microRNAs (miRNAs) in tumorigenesis, we hypothesized thatmiRNAscould play important roles in the response of tumors tomTORinhibitors. Long-term rapamycin treatment showed extensive reprogramming of miRNA expression, characterized by up-regulation of miR-17-92 and related clusters and down-regulation of tumor suppressor miRNAs. Inhibition of members of the miR-17-92 clusters or delivery of tumor suppressor miRNAs restored sensitivity to rapamycin. This study identifies miRNAs as new downstream components of the mTOR-signaling pathway, which may determine the response of tumors to mTOR inhibitors. It also identifies potential markers to assess the efficacy of treatment and provides novel therapeutic targets to treat rapamycin-resistant tumors.

Original languageEnglish
Pages (from-to)6034-6044
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number9
DOIs
Publication statusPublished - 1 Mar 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Totary-Jain, H., Sanoudou, D., Ben-Dov, I. Z., Dautriche, C. N., Guarnieri, P., Marx, S. O., Tuschl, T., & Marks, A. R. (2013). Reprogramming of the MicroRNA transcriptome mediates resistance to rapamycin. Journal of Biological Chemistry, 288(9), 6034-6044. https://doi.org/10.1074/jbc.M112.416446