GSK2801 Reverses Paclitaxel Resistance in Anaplastic Thyroid Cancer Cell Lines through MYCN Downregulation

Abstract

Anaplastic thyroid cancer (ATC) is a very rare, but extremely aggressive form of thyroid malignancy, responsible for the highest mortality rate registered for thyroid cancer. Treatment with taxanes (such as paclitaxel) is an important approach in counteracting ATC or slowing its progression in tumors without known genetic aberrations or those which are unresponsive to other treatments. Unfortunately, resistance often develops and, for this reason, new therapies that overcome taxane resistance are needed. In this study, effects of inhibition of several bromodomain proteins in paclitaxel-resistant ATC cell lines were investigated. GSK2801, a specific inhibitor of BAZ2A, BAZ2B and BRD9, was effective in resensitizing cells to paclitaxel. In fact, when used in combination with paclitaxel, it was able to reduce cell viability, block the ability to form colonies in an anchor-independent manner, and strongly decrease cell motility. After RNA-seq following treatment with GSK2801, we focused our attention on MYCN. Based on the hypothesis that MYCN was a major downstream player in the biological effects of GSK2801, we tested a specific inhibitor, VPC-70619, which showed effective biological effects when used in association with paclitaxel. This suggests that the functional deficiency of MYCN determines a partial resensitization of the cells examined and, ultimately, that a substantial part of the effect of GSK2801 results from inhibition of MYCN expression.

Dihydrotanshinone I exhibits antitumor effects via β-catenin downregulation in papillary thyroid cancer cell lines

“…The Wnt signaling pathway plays an important role during development and regeneration of adult tissue homeostasis 34 . Abnormal regulation of this pathway is closely associated with several non-cancer diseases and cancer diseases 35 , as also observed by our group 36 , suggesting that the Wnt signaling pathway is an attractive target for disease treatment 37 – 40 . The canonical Wnt pathway is generally highly conserved and is activated through the binding of extracellular Wnt ligands to membrane receptors by autocrine/paracrine methods.…”

“…Reads were aligned to the reference genome and the RNA-seq analysis plugin was run on the Torrent Suite Server (Thermo Fisher Scientific). As previously described 36 , for further analysis, we selected effective data for those with FPKM values > 0.5 and log2 fold-change > 1.5 or < − 1.5. In the evaluation of commonly up or downregulated genes, the cut-offs were increased to − 3 and + 3 in order to obtain more representative results.…”