title: Reprogramming of the microRNA transcriptome mediates resistance to rapamycin.
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 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.
authors.affiliation: Department of Physiology and Cellular Biophysics, the Clyde and Helen Wu Center for Molecular Cardiology, Columbia University, New York, New York 10032, USA. ht2167@columbia.edu
authors.forename: Hana
authors.initials: H
authors.lastname: Totary-Jain
authors.forename: Despina
authors.initials: D
authors.lastname: Sanoudou
authors.forename: Iddo Z
authors.initials: IZ
authors.lastname: Ben-Dov
authors.forename: Cula N
authors.initials: CN
authors.lastname: Dautriche
authors.forename: Paolo
authors.initials: P
authors.lastname: Guarnieri
authors.forename: Steven O
authors.initials: SO
authors.lastname: Marx
authors.forename: Thomas
authors.initials: T
authors.lastname: Tuschl
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D059467:Transcriptome / Q000187:drug effects*
chemical_list: D000903:Antibiotics, Antineoplastic; C575895:MIRN17-92 microRNA, mouse; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus