TY - JOUR
T1 - Targeting of RET oncogene by naphthalene diimide-mediated gene promoter G-quadruplex stabilization exerts anti-tumor activity in oncogene-addicted human medullary thyroid cancer
AU - Lopergolo, Alessia
AU - Perrone, Rosalba
AU - Tortoreto, Monica
AU - Doria, Filippo
AU - Beretta, Giovanni L.
AU - Zuco, Valentina
AU - Freccero, Mauro
AU - Borrello, Maria Grazia
AU - Lanzi, Cinzia
AU - Richter, Sara N.
AU - Zaffaroni, Nadia
AU - Folini, Marco
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - G-quadruplex
KW - Gene promoter
KW - Medullary thyroid cancer
KW - Naphthalene diimide
KW - RET oncogene
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U2 - 10.18632/oncotarget.10105
DO - 10.18632/oncotarget.10105
M3 - Article
AN - SCOPUS:84981354744
VL - 7
SP - 49649
EP - 49663
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 31
ER -