TY - JOUR
T1 - Digitalis-like compounds facilitate non-medullary thyroid cancer redifferentiation through intracellular Ca2+, FOS, and autophagy-dependent pathways
AU - Tesselaar, Marika H.
AU - Crezee, Thomas
AU - Swarts, Herman G.
AU - Gerrits, Danny
AU - Boerman, Otto C.
AU - Koenderink, Jan B.
AU - Stunnenberg, Hendrik G.
AU - Netea, Mihai G.
AU - Smit, Johannes W.A.
AU - Netea-Maier, Romana T.
AU - Plantinga, Theo S.
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2017/1
Y1 - 2017/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85010002099&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-16-0460
DO - 10.1158/1535-7163.MCT-16-0460
M3 - Article
C2 - 27837029
AN - SCOPUS:85010002099
SN - 1535-7163
VL - 16
SP - 169
EP - 181
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 1
ER -