Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing

Sonia Melo, Alberto Villanueva, Catia Moutinho, Veronica Davalos, Riccardo Spizzo, Cristina Ivan, Simona Rossi, Fernando Setien, Oriol Casanovas, Laia Simo-Riudalbas, Javier Carmona, Jordi Carrere, August Vidal, Alvaro Aytes, Sara Puertas, Santiago Ropero, Raghu Kalluri, Carlo M. Croce, George A. Calinc, Manel Esteller

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)4394-4399
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number11
DOIs
Publication statusPublished - Mar 15 2011

Keywords

  • Non-coding RNA
  • Pharmacogenetics
  • Therapy
  • Transformation

ASJC Scopus subject areas

  • General

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