Abstract:
:Medullary thyroid cancer (MTC) is a tumor highly resistant to chemo- and radiotherapy. Drug resistance can be induced by epigenetic changes such as aberrant DNA methylation. To overcome drug resistance, we explored a promising approach based on the use of 5-aza-2'-deoxycytidine (AZA), a demethylating agent, in combination with the mTOR inhibitor everolimus in MTC cells (MZ-CRC-1 and TT). This combined treatment showed a strong synergistic antiproliferative activity through the induction of apoptosis. The effect of everolimus and/or AZA on genome-wide expression profiling was evaluated by Illumina BeadChip in MZ-CRC-1 cells. An innovative bioinformatic pipeline identified four potential molecular pathways implicated in the synergy between AZA and everolimus: PI3K-Akt signaling, the neurotrophin pathway, ECM/receptor interaction, and focal adhesion. Among these, the neurotrophin signaling pathway was most directly involved in apoptosis, through the overexpression of NGFR and Bax genes. The increased expression of genes involved in the NGFR-MAPK10-TP53-Bax/Bcl2 pathway during incubation with AZA plus everolimus was validated by western blotting in MZ-CRC-1 cells. Interestingly, addition of a neutralizing anti-NGFR antibody inhibited the synergistic cytotoxic activity between AZA and everolimus. These results open a new therapeutic scenario for MTC and potentially other neuroendocrine tumors, where therapy with mTOR inhibitors is currently approved.
journal_name
Mol Oncoljournal_title
Molecular oncologyauthors
Vitale G,Dicitore A,Pepe D,Gentilini D,Grassi ES,Borghi MO,Gelmini G,Cantone MC,Gaudenzi G,Misso G,Di Blasio AM,Hofland LJ,Caraglia M,Persani Ldoi
10.1002/1878-0261.12070subject
Has Abstractpub_date
2017-08-01 00:00:00pages
1007-1022issue
8eissn
1574-7891issn
1878-0261journal_volume
11pub_type
杂志文章abstract::Our limited understanding of the biological impact of the whole spectrum of early breast lesions together with a lack of accurate molecular-based risk criteria for the diagnosis and assignment of prognostic significance to biopsy findings presents an important problem in the clinical management of patients harboring p...
journal_title:Molecular oncology
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journal_title:Molecular oncology
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pub_type: 杂志文章,评审
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journal_title:Molecular oncology
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pub_type: 杂志文章,评审
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journal_title:Molecular oncology
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