mTOR Inhibition promotes TTF1-dependent redifferentiation and restores iodine uptake in thyroid carcinoma cell lines.
METHODS
Redifferentiation of thyroid carcinoma cells has the potential to increase the efficacy of radioactive iodine therapy in treatment-refractory, nonmedullary thyroid carcinoma (TC), leading to an improved disease outcome. Mammalian target of rapamycin (mTOR) is a key regulator of cell fate affecting survival and differentiation, with autophagy and inflammation as prominent downstream pathways.


METHODS
The effects of mTOR inhibition were studied for its redifferentiation potential of the human TC cell lines BC-PAP, FTC133, and TPC1 by assessment of mRNA and protein expression of thyroid-specific genes and by performance of iodine uptake assays.


RESULTS
In thyroid transcription factor 1 (TTF1)-expressing cell lines, mTOR inhibition promoted redifferentiation of TC cells by the up-regulation of human sodium-iodine symporter mRNA and protein expression. Furthermore, these cells exhibited markedly elevated iodine uptake capacity. Surprisingly, this redifferentiation process was not mediated by autophagy induced during mTOR inhibition or by inflammatory mediators but through transcriptional effects at the level of TTF1 expression. Accordingly, small interfering RNA inhibition of TTF1 completely abrogated the induction of human sodium-iodine symporter by mTOR inhibition.


CONCLUSIONS
The present study has identified the TTF1-dependent molecular mechanisms through which the inhibition of mTOR leads to the redifferentiation of TC cells and subsequently to increased radioactive iodine uptake.
Departments of Internal Medicine (T.S.P., B.H., M.G.N., L.A.B.J., A.R.M.M.H., J.W.A.S., R.T.N.-M.) and Nuclear Medicine (D.G., W.J.G.O., O.C.B.) and Division of Endocrinology (T.S.P., A.R.M.M.H., J.W.A.S., R.T.N.-M.), Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands; and Division of Endocrinology, Diabetes, and Metabolism (R.E.S., B.R.H.), University of Colorado Denver, Aurora, Colorado 80045.
Theo S
TS
Plantinga
Bas
B
Heinhuis
Danny
D
Gerrits
Mihai G
MG
Netea
Leo A B
LA
Joosten
Ad R M M
AR
Hermus
Wim J G
WJ
Oyen
Rebecca E
RE
Schweppe
Bryan R
BR
Haugen
Otto C
OC
Boerman
Johannes W A
JW
Smit
Romana T
RT
Netea-Maier
D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D018265:Carcinoma, Papillary, Follicular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology; D007457:Iodine Radioisotopes / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors
D004268:DNA-Binding Proteins; D015850:Interleukin-6; D007457:Iodine Radioisotopes; C504003:TTF1 protein, human; D014157:Transcription Factors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus