title: Switching from MAPK-dependent to MAPK-independent repression of the sodium-iodide symporter in 2D and 3D cultured normal thyroid cells.
abstract: Loss of sodium-iodide symporter (NIS) expression in thyroid tumour cells primarily caused by constitutive MAPK pathway activation is often refractory to small molecule MAPK inhibitors. Suggested mechanisms are rebound MAPK signalling and activation of alternative signalling pathways. Here we provide evidence that failure to recover down-regulated NIS by MEK inhibition is not specific to tumour cells. NIS mRNA levels remained repressed in TSH-stimulated primary thyroid cells co-treated with epidermal growth factor (EGF) and pan-MEK inhibitor U0126 in the presence of 5% fetal bovine serum or, independently of serum, in 3D cultured thyroid follicles. This led to inhibited iodide transport and iodination. In contrast, U0126 restituted thyroglobulin synthesis in EGF-treated follicular cells. Serum potentiated TSH-stimulated NIS expression in 2D culture. U0126 blocked down-regulation of NIS only in serum-starved cells with a diminished TSH response. Together, this suggests that morphogenetic signals modify the expression of NIS and recovery response to MEK inhibition.
authors: Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden. Electronic address: camilla.ingeson@gu.su.
authors: Camilla
authors: C
authors: Ingeson-Carlsson
authors: Mikael
authors: M
authors: Nilsson
mesh_terms: D000818:Animals; D001692:Biological Transport; D002070:Butadienes / Q000494:pharmacology; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004815:Epidermal Growth Factor / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015870:Gene Expression; D020868:Gene Silencing; D007454:Iodides / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034421:Sus scrofa; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology*; D000099209:Sodium-Iodide Symporters
chemical_list: D002070:Butadienes; D016895:Culture Media, Serum-Free; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D007454:Iodides; D020930:MAP Kinase Kinase Kinases; D009570:Nitriles; D012333:RNA, Messenger; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C113580:U 0126
keywords: EGF; EMT; ERK1/2; FBS; IGF-1; Iodide transport; LY294002; MAPK; MAPK kinase; MEK; MEK inhibitor; MEK1/2 inhibitor; NIS; PD; PI3K; PI3K inhibitor; PTC; TER; TGF-beta; TSH; Tg; Thyroid; U0126; epidermal growth factor; epithelial to mesenchymal transition; extracellular-signal regulated kinase 1/2; fetal bovine serum; insulin-like growth factor-1; mitogen-activated protein kinase; papillary thyroid cancer; phosphoinositide-3-kinase; potential difference; sodium iodide symporter; thyroglobulin; thyroid stimulation hormone (thyrotropin); transepithelial resistance; transforming growth factor-beta