TY - JOUR
T1 - Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing
AU - Melo, Sonia
AU - Villanueva, Alberto
AU - Moutinho, Catia
AU - Davalos, Veronica
AU - Spizzo, Riccardo
AU - Ivan, Cristina
AU - Rossi, Simona
AU - Setien, Fernando
AU - Casanovas, Oriol
AU - Simo-Riudalbas, Laia
AU - Carmona, Javier
AU - Carrere, Jordi
AU - Vidal, August
AU - Aytes, Alvaro
AU - Puertas, Sara
AU - Ropero, Santiago
AU - Kalluri, Raghu
AU - Croce, Carlo M.
AU - Calinc, George A.
AU - Esteller, Manel
PY - 2011/3/15
Y1 - 2011/3/15
N2 - MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression at the posttranscriptional level and are critical for many cellular pathways. The disruption of miRNAs and their processing machineries also contributes to the development of human tumors. A common scenario for miRNA expression in carcinogenesis is emerging that shows that impaired miRNA production and/or down-regulation of these transcripts occurs in many neoplasms. Several of these lost miRNAs have tumor-suppressor features, so strategies to restore their expression globally in malignancies would be a welcome addition to the current therapeutic arsenal against cancer. Herein, we show that the small molecule enoxacin, a fluoroquinolone used as an antibacterial compound, enhances the production of miRNAs with tumor suppressor functions by binding to the miRNA biosynthesis protein TAR RNA-binding protein 2 (TRBP). The use of enoxacin in human cell cultures and xenografted, orthotopic, and metastatic mouse models reveals a TRBP-dependent and cancer-specific growth-inhibitory effect of the drug. These results highlight the key role of disrupted miRNA expression patterns in tumorigenesis, and suggest a unique strategy for restoring the distorted microRNAome of cancer cells to a more physiological setting.
AB - MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression at the posttranscriptional level and are critical for many cellular pathways. The disruption of miRNAs and their processing machineries also contributes to the development of human tumors. A common scenario for miRNA expression in carcinogenesis is emerging that shows that impaired miRNA production and/or down-regulation of these transcripts occurs in many neoplasms. Several of these lost miRNAs have tumor-suppressor features, so strategies to restore their expression globally in malignancies would be a welcome addition to the current therapeutic arsenal against cancer. Herein, we show that the small molecule enoxacin, a fluoroquinolone used as an antibacterial compound, enhances the production of miRNAs with tumor suppressor functions by binding to the miRNA biosynthesis protein TAR RNA-binding protein 2 (TRBP). The use of enoxacin in human cell cultures and xenografted, orthotopic, and metastatic mouse models reveals a TRBP-dependent and cancer-specific growth-inhibitory effect of the drug. These results highlight the key role of disrupted miRNA expression patterns in tumorigenesis, and suggest a unique strategy for restoring the distorted microRNAome of cancer cells to a more physiological setting.
KW - Non-coding RNA
KW - Pharmacogenetics
KW - Therapy
KW - Transformation
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U2 - 10.1073/pnas.1014720108
DO - 10.1073/pnas.1014720108
M3 - Article
C2 - 21368194
AN - SCOPUS:79952717616
VL - 108
SP - 4394
EP - 4399
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 11
ER -