MTOR downregulates iodide uptake in thyrocytes.
Phosphoinositide-3-kinase (PI3K) inhibition increases functional sodium iodide symporter (NIS) expression in both FRTL-5 rat thyroid cell line and papillary thyroid cancer lineages. In several cell types, the stimulation of PI3K results in downstream activation of the mechanistic target of rapamycin (MTOR), a serine-threonine protein kinase that is a critical regulator of cellular metabolism, growth, and proliferation. MTOR activation is involved in the regulation of thyrocyte proliferation by TSH. Here, we show that MTOR inhibition by rapamycin increases iodide uptake in TSH-stimulated PCCL3 thyroid cell line, although the effect of rapamycin was less pronounced than PI3K inhibition. Thus, NIS inhibitory pathways stimulated by PI3K might also involve the activation of proteins other than MTOR. Insulin downregulates iodide uptake and NIS protein expression even in the presence of TSH, and both effects are counterbalanced by MTOR inhibition. NIS protein expression levels were correlated with iodide uptake ability, except in cells treated with TSH in the absence of insulin, in which rapamycin significantly increased iodide uptake, while NIS protein levels remained unchanged. Rapamycin avoids the activation of both p70 S6 and AKT kinases by TSH, suggesting the involvement of MTORC1 and MTORC2 in TSH effect. A synthetic analog of rapamycin (everolimus), which is clinically used as an anticancer agent, was able to increase rat thyroid iodide uptake in vivo. In conclusion, we show that MTOR kinase participates in the control of thyroid iodide uptake, demonstrating that MTOR not only regulates cell survival, but also normal thyroid cell function both in vitro and in vivo.
de Souza
Elaine Cristina Lima
EC
Laboratório de Fisiologia Endócrina Doris Rosenthal, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Padrón
Alvaro Souto
AS
Braga
William Miranda Oliveira
WM
de Andrade
Bruno Moulin
BM
Vaisman
Mário
M
Nasciutti
Luiz Eurico
LE
Ferreira
Andrea Claudia Freitas
AC
de Carvalho
Denise Pires
DP
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D007457:Iodine Radioisotopes; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D012974:Sodium Iodide / Q000378:metabolism*; D027981:Symporters / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology; D058570:TOR Serine-Threonine Kinases; D013961:Thyroid Gland / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013972:Thyrotropin / Q000494:pharmacology; D000099209:Sodium-Iodide Symporters
D002867:Chromones; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus; D012974:Sodium Iodide; D027981:Symporters; D058570:TOR Serine-Threonine Kinases; D013972:Thyrotropin; D000099209:Sodium-Iodide Symporters; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546845:mTOR protein, rat