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Digitalis-like compounds restore hNIS expression and iodide uptake capacity in anaplastic thyroid cancer.

Digitalis-like compounds restore hNIS expression and iodide uptake capacity in anaplastic thyroid cancer.
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Tesselaar MH, Crezee T, Schuurmans I, Gerrits D, Nagarajah J, Boerman OC, van Engen-van Grunsven I, Smit JWA, Netea-Maier RT, Plantinga TS,


Tesselaar MH, Crezee T, Schuurmans I, Gerrits D, Nagarajah J, Boerman OC, van Engen-van Grunsven I, Smit JWA, Netea-Maier RT, Plantinga TS, (click to view)

Tesselaar MH, Crezee T, Schuurmans I, Gerrits D, Nagarajah J, Boerman OC, van Engen-van Grunsven I, Smit JWA, Netea-Maier RT, Plantinga TS,

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Journal of nuclear medicine : official publication, Society of Nuclear Medicine 2017 12 14() pii 10.2967/jnumed.117.200675

Abstract

Purpose: Anaplastic thyroid cancer (ATC) is a rare malignancy that accounts for 1-2% of all thyroid cancers. ATC is one of the most aggressive human cancers, with rapid growth, tumor invasion and development of distant metastases. The median survival is only 5 months and the 1-year survival is less than 20%. Moreover, as a result of severe dedifferentiation including the loss of human sodium iodide symporter (hNIS) expression, radioactive iodide (RAI) therapy is ineffective. Recently, we have demonstrated beneficial effects of autophagy activating digitalis-like compounds (DLCs) on redifferentiation and concomitant restoration of iodide uptake in RAI-refractory papillary and follicular thyroid cancer cell lines. In the current study, the effects of DLCs on differentiation and proliferation of ATC cell lines were investigated. Methods: Autophagy activity was assessed in ATC patient tissues by immunofluorescent stainings for the autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3). In addition, the effect of autophagy activating DLCs on proliferation, gene expression profile and iodide uptake capacity of ATC cell lines was studied. Results: Diminished autophagy activity was observed in ATC tissues and in vitro treatment of ATC cell lines with DLCs robustly restored hNIS and thyroglobulin expression and iodide uptake capacity. In addition, proliferation was strongly reduced by induction of cell cycle arrest and, to some extent, cell death. Mechanistically, reactivation of functional hNIS expression could be attributed to activation of the transcription factors activating transcription factor 3 (ATF3) and proto-oncogene c-fos (cFOS). Conclusion: DLCs could represent a promising adjunctive therapy for restoring iodide avidity within the full spectrum from RAI-refractory dedifferentiated to anaplastic thyroid cancer.

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