Digitalis-like compounds facilitate non-medullary thyroid cancer redifferentiation through intracellular Ca2+, FOS, and autophagy-dependent pathways

Marika H. Tesselaar, Thomas Crezee, Herman G. Swarts, Danny Gerrits, Otto C. Boerman, Jan B. Koenderink, Hendrik G. Stunnenberg, Mihai G. Netea, Johannes W.A. Smit, Romana T. Netea-Maier, Theo S. Plantinga

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

18 Citaten (Scopus)

Samenvatting

Up to 20%-30% of patients with metastatic non-medullary thyroid cancer have persistent or recurrent disease resulting from tumor dedifferentiation. Tumor redifferentiation to restore sensitivity to radioactive iodide (RAI) therapy is considered a promising strategy to overcome RAI resistance. Autophagy has emerged as an important mechanism in cancer dedifferentiation. Here, we demonstrate the therapeutic potential of autophagy activators for redifferentiation of thyroid cancer cell lines. Five autophagy-activating compounds, all known as digitalis-like compounds, restored hNIS expression and iodide uptake in thyroid cancer cell lines. Upregulation of hNIS was mediated by intracellular Ca2? and FOS activation. Cell proliferation was inhibited by downregulating AKT1 and by induction of autophagy and p21-dependent cellcycle arrest. Digitalis-like compounds, also designated as cardiac glycosides for their well-characterized beneficial effects in the treatment of heart disease, could therefore represent a promising repositioned treatment modality for patients with RAI-refractory thyroid carcinoma.

Originele taal-2Engels
Pagina's (van-tot)169-181
Aantal pagina's13
TijdschriftMolecular Cancer Therapeutics
Volume16
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - jan. 2017
Extern gepubliceerdJa

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