Antitumor Effects of Proteasome Inhibition in Anaplastic Thyroid Carcinoma

Abstract

The ubiquitin-proteasome pathway has been identified as a potential molecular target for cancer therapy. In this study, we investigated the effect of the proteasome inhibitor bortezomib on anaplastic thyroid carcinoma (ATC) characterized by complete refractoriness to multimodal therapeutic approaches. Methods: The ATC cell lines C643 and SW1736 were treated with bortezomib (1 nM to 1 mM) for 12-72 h. Thereafter, growth inhibition was analyzed by thymidine uptake experiments and determination of the viable cell number. Apoptosis was measured and a cell cycle analysis was done. Using gene chip analysis and the real-time quantitative PCR system, we measured transcriptional changes. The activity of the nuclear factor (NF)-kB and p53 signal transduction pathways was monitored using the reporter constructs pNF-kB-TA-Luc and pp53-TA-Luc in the luciferase activity assay. Uptake measurements using 3 H-FDG, 14 C-aminoisobutyric acid, and Na 125 iodide were performed to investigate metabolic changes and iodide symporter activity in vitro. Moreover, the 18 F-FDG uptake was evaluated in ATC tumor-bearing nude mice 1 or 2 d after treatment with bortezomib. Results: Bortezomib induced growth inhibition, apoptosis, and G 2 -M cell cycle arrest associated with upregulation of p21 CIP1/WAF1 expression in SW1736 and C643 cells. Moreover, the glucose metabolism and aminoisobutyric acid uptake significantly decreased in vitro in both of the ATC cell lines in vivo only in SW1736 tumors at 2 d after the bortezomib treatment. The transcriptional profile in bortezomib-treated SW1736 and C643 cells revealed increased expression of genes involved in stress response, apoptosis, regulation of the cell cycle, and differentiation. Using real-time quantitative PCR for the quantification of gene expression, we additionally noticed upregulation of the tumor necrosis factor-related apoptosis-inducing ligand and the thyroid-specific transcription factors Pax8 and TTF-1, leading to expression of the thyroid-specific target genes thyroglobulin, sodium iodide symporter, thyroperoxidase, and thyroid-stimulating hormone receptor and to a moderate accumulation of iodide in ATC cells. Conclusion: On the basis of our data, bortezomib represents a promising antineoplastic agent for the treatment of ATC. To improve the clinical outcome, further investigation into the potential of bortezomib therapy of thyroid cancer is clearly warranted.

Aberrant Lipid Metabolism in Anaplastic Thyroid Carcinoma Reveals Stearoyl CoA Desaturase 1 as a Novel Therapeutic Target

“…Proteosome inhibitors have also been investigated in the context of ATC as antitumor agents (38,39). Our results demonstrate that both drugs when used in combination significantly decrease tumor growth and induce tumor cell death in vitro and in vivo (Figures 4 -6 and Supplemental Figures 1 and 2).…”

Carfilzomib is an effective anticancer agent in anaplastic thyroid cancer

“…Bortezomib, the first inhibitor of the UPP to be used in clinical studies, has been extensively studied for both hematological and solid cancers, including thyroid cancer (Hideshima et al 2001, Papandreou et al 2004, Mitsiades et al 2006, Altmann et al 2012, Wunderlich et al 2012. Results of recent preclinical studies have also indicated that bortezomib inhibits ATC cell proliferation and induces caspase-dependent apoptosis in vitro, with potent antitumor effects in vivo as well (Mitsiades et al 2006, Conticello et al 2007, Altmann et al 2012, Wunderlich et al 2012.…”

“…Results of recent preclinical studies have also indicated that bortezomib inhibits ATC cell proliferation and induces caspase-dependent apoptosis in vitro, with potent antitumor effects in vivo as well (Mitsiades et al 2006, Conticello et al 2007, Altmann et al 2012, Wunderlich et al 2012. The clinical efficacy of bortezomib, however, is challenged by the rapid development of drug resistance, as it is not an irreversible proteasome inhibitor like carfilzomib, and also by the dose-limiting neurotoxicity associated with bortezomib treatment (Ruckrich et al 2009, Jain et al 2011.…”

Anaplastic thyroid cancer

“…Proteosome inhibitors, such as bortezomib, have been shown to aid apoptosis and decrease tumor proliferation in preclinical studies [34].…”