Digitalis-like Compounds Facilitate Non-Medullary Thyroid Cancer Redifferentiation through Intracellular Ca2+, FOS, and Autophagy-Dependent Pathways.
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 cell-cycle 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. Mol Cancer Ther; 16(1); 169-81. ©2016 AACR.
Department of Pathology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
Marika H
MH
Tesselaar
Department of Pathology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
Thomas
T
Crezee
Department of Pharmacology & Toxicology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
Herman G
HG
Swarts
Department of Radiology & Nuclear Medicine, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
Danny
D
Gerrits
Department of Radiology & Nuclear Medicine, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
Otto C
OC
Boerman
Department of Pharmacology & Toxicology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
Jan B
JB
Koenderink
Department of Molecular Biology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
Hendrik G
HG
Stunnenberg
Department of Internal Medicine, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
Mihai G
MG
Netea
Department of Internal Medicine, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
Johannes W A
JW
Smit
Department of Internal Medicine, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
Romana T
RT
Netea-Maier
Department of Pathology, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands. theo.plantinga@radboudumc.nl.
Theo S
TS
Plantinga
D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D004070:Digitalis / Q000737:chemistry*; D020869:Gene Expression Profiling; D006801:Humans; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D027981:Symporters / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D059467:Transcriptome; D000099209:Sodium-Iodide Symporters
D051700:Activating Transcription Factor 3; D000972:Antineoplastic Agents, Phytogenic; D002118:Calcium; D016760:Proto-Oncogene Proteins c-fos; D027981:Symporters; D000099209:Sodium-Iodide Symporters