TY - JOUR T1 - Reprogramming of the microRNA transcriptome mediates resistance to rapamycin JF - J Biol ChemJ Biol ChemJ Biol Chem Y1 - 2013 A1 - Totary-Jain, H. A1 - Sanoudou, D. A1 - Ben-Dov, I. Z. A1 - Dautriche, C. N. A1 - Guarnieri, P. A1 - Marx, S. O. A1 - Tuschl, T. A1 - Marks, A. R. KW - Animals KW - Antibiotics, Antineoplastic/*pharmacology KW - Cell Line, Tumor KW - Drug Resistance, Neoplasm/*drug effects KW - Gene Expression Regulation, Neoplastic/*drug effects KW - Mice KW - MicroRNAs/*biosynthesis KW - Neoplasm Proteins/metabolism KW - RNA, Neoplasm/*biosynthesis KW - Signal Transduction/drug effects KW - Sirolimus/*pharmacology KW - Time Factors KW - TOR Serine-Threonine Kinases/metabolism KW - Transcriptome/*drug effects AB - 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 that miRNAs could play important roles in the response of tumors to mTOR inhibitors. 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. VL - 288 SN - 1083-351X (Electronic)0021-9258 (Linking) N1 - Totary-Jain, HanaSanoudou, DespinaBen-Dov, Iddo ZDautriche, Cula NGuarnieri, PaoloMarx, Steven OTuschl, ThomasMarks, Andrew RengK99 HL109133/HL/NHLBI NIH HHS/K99HL109133/HL/NHLBI NIH HHS/F32HL088815/HL/NHLBI NIH HHS/Howard Hughes Medical Institute/F32 HL088815/HL/NHLBI NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't2013/01/10 06:00J Biol Chem. 2013 Mar 1;288(9):6034-44. doi: 10.1074/jbc.M112.416446. Epub 2013 Jan 8. U2 - 3585042 JO - The Journal of biological chemistryThe Journal of biological chemistry ER -