PMID- 24712572
OWN - NLM
STAT- MEDLINE
DCOM- 20140929
LR  - 20211203
IS  - 1945-7197 (Electronic)
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 99
IP  - 7
DP  - 2014 Jul
TI  - mTOR Inhibition promotes TTF1-dependent redifferentiation and restores iodine 
      uptake in thyroid carcinoma cell lines.
PG  - E1368-75
LID - 10.1210/jc.2014-1171 [doi]
AB  - CONCEPT: 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. CONCLUSION: 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.
FAU - Plantinga, Theo S
AU  - Plantinga TS
AD  - 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.
FAU - Heinhuis, Bas
AU  - Heinhuis B
FAU - Gerrits, Danny
AU  - Gerrits D
FAU - Netea, Mihai G
AU  - Netea MG
FAU - Joosten, Leo A B
AU  - Joosten LA
FAU - Hermus, Ad R M M
AU  - Hermus AR
FAU - Oyen, Wim J G
AU  - Oyen WJ
FAU - Schweppe, Rebecca E
AU  - Schweppe RE
FAU - Haugen, Bryan R
AU  - Haugen BR
FAU - Boerman, Otto C
AU  - Boerman OC
FAU - Smit, Johannes W A
AU  - Smit JW
FAU - Netea-Maier, Romana T
AU  - Netea-Maier RT
LA  - eng
GR  - P30 CA046934/CA/NCI NIH HHS/United States
GR  - R01 CA175994/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140408
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Interleukin-6)
RN  - 0 (Iodine Radioisotopes)
RN  - 0 (TTF1 protein, human)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Autophagy/drug effects/genetics
MH  - Carcinoma, Papillary, Follicular/genetics/*metabolism/pathology
MH  - Cell Differentiation/*drug effects/genetics
MH  - Cell Line, Tumor
MH  - DNA-Binding Proteins/*physiology
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Inflammation/genetics/metabolism
MH  - Interleukin-6/pharmacology
MH  - Iodine Radioisotopes/*metabolism
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Thyroid Neoplasms/genetics/*metabolism/pathology
MH  - Transcription Factors
PMC - PMC5393487
EDAT- 2014/04/10 06:00
MHDA- 2014/09/30 06:00
PMCR- 2015/07/01
CRDT- 2014/04/10 06:00
PHST- 2014/04/10 06:00 [entrez]
PHST- 2014/04/10 06:00 [pubmed]
PHST- 2014/09/30 06:00 [medline]
PHST- 2015/07/01 00:00 [pmc-release]
AID - 14-1171 [pii]
AID - 10.1210/jc.2014-1171 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2014 Jul;99(7):E1368-75. doi: 10.1210/jc.2014-1171. Epub 
      2014 Apr 8.