Identification of small molecules that suppress microRNA function and reverse tumorigenesis.
MicroRNAs (miRNAs) act in post-transcriptional gene silencing and are proposed to function in a wide spectrum of pathologies, including cancers and viral diseases. Currently, to our knowledge, no detailed mechanistic characterization of small molecules that interrupt miRNA pathways have been reported. In screening a small chemical library, we identified compounds that suppress RNA interference activity in cultured cells. Two compounds were characterized; one impaired Dicer activity while the other blocked small RNA-loading into an Argonaute 2 (AGO2) complex. We developed a cell-based model of miRNA-dependent tumorigenesis, and using this model, we observed that treatment of cells with either of the two compounds effectively neutralized tumor growth. These findings indicate that miRNA pathway-suppressing small molecules could potentially reverse tumorigenesis.
Molecular Virology Section, Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
Koichi
K
Watashi
Man Lung
ML
Yeung
Matthew F
MF
Starost
Ramachandra S
RS
Hosmane
Kuan-Teh
KT
Jeang
D016475:3T3 Cells; D000818:Animals; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*; D010641:Phenotype; D034622:RNA Interference
D035683:MicroRNAs