Targeting of RET oncogene by naphthalene diimide-mediated gene promoter G-quadruplex stabilization exerts anti-tumor activity in oncogene-addicted human medullary thyroid cancer
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Alessia Lopergolo1,*, Rosalba Perrone2,*, Monica Tortoreto1, Filippo Doria3, Giovanni L. Beretta1, Valentina Zuco1, Mauro Freccero3, Maria Grazia Borrello1, Cinzia Lanzi1, Sara N. Richter2, Nadia Zaffaroni1, Marco Folini1
1Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milano, Italy
2Department of Molecular Medicine, University of Padua, 35121, Padova, Italy
3Department of Chemistry, University of Pavia, 27100, Pavia, Italy
*These authors have contributed equally to this work
Marco Folini, email: firstname.lastname@example.org.
Sara N. Richter, email: email@example.com.
Keywords: gene promoter, G-quadruplex, medullary thyroid cancer, naphthalene diimide, RET oncogene
Received: October 22, 2015 Accepted: May 13, 2016 Published: June 16, 2016
Medullary thyroid cancer (MTC) relies on the aberrant activation of RET proto-oncogene. 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.
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