Targeting of RET oncogene by naphthalene diimide-mediated gene promoter G-quadruplex stabilization exerts anti-tumor activity in oncogene-addicted human medullary thyroid cancer

Alessia Lopergolo, Rosalba Perrone, Monica Tortoreto, Filippo Doria, Giovanni L. Beretta, Valentina Zuco, Mauro Freccero, Maria Grazia Borrello, Cinzia Lanzi, Sara N. Richter, Nadia Zaffaroni, Marco Folini

Research output: Contribution to journalArticlepeer-review

Abstract

Medullary thyroid cancer (MTC) relies on the aberrant activation of RET protooncogene. Though targeted approaches (i.e., tyrosine kinase inhibitors) are available, the absence of complete responses and the onset of resistance mechanisms indicate the need for novel therapeutic interventions. Due to their role in regulation of gene expression, G-quadruplexes (G4) represent attractive targets amenable to be recognized or stabilized by small molecules. Here, we report that exposure of MTC cells to a tri-substituted naphthalene diimide (NDI) resulted in a significant antiproliferative activity paralleled by inhibition of RET expression. Biophysical analysis and gene reporter assays showed that impairment of RET expression was consequent to the NDI-mediated stabilization of the G4 forming within the gene promoter. We also showed for the first time that systemic administration of the NDI in mice xenotransplanted with MTC cells resulted in a remarkable inhibition of tumor growth in vivo. Overall, our findings indicate that NDI-dependent RET G4 stabilization represents a suitable approach to control RET transcription and delineate the rationale for the development of G4 stabilizing-based treatments for MTC as well as for other tumors in which RET may have functional and therapeutic implications.

Original languageEnglish
Pages (from-to)49649-49663
Number of pages15
JournalOncotarget
Volume7
Issue number31
DOIs
Publication statusPublished - 2016

Keywords

  • G-quadruplex
  • Gene promoter
  • Medullary thyroid cancer
  • Naphthalene diimide
  • RET oncogene

ASJC Scopus subject areas

  • Oncology

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