scholarly journals Modulation of sodium iodide symporter expression and function by LY294002, Akti-1/2 and Rapamycin in thyroid cells

2012 ◽  
Vol 19 (3) ◽  
pp. 291-304 ◽  
Author(s):  
Yu-Yu Liu ◽  
Xiaoli Zhang ◽  
Matthew D Ringel ◽  
Sissy M Jhiang
Keyword(s):  
Sodium Iodide Symporter ◽  
Efflux Rate ◽  
Iodide Uptake ◽  
Thyroid Cells ◽  
Thyroid Cancers ◽  
Protein Levels ◽  
Iodide Transport ◽  
Pi3k Inhibition ◽  
And Function ◽  
Selective Increase

The selective increase of Na+/I−symporter (NIS)-mediated active iodide uptake in thyroid cells allows the use of radioiodine I131for diagnosis and targeted treatment of thyroid cancers. However, NIS-mediated radioiodine accumulation is often reduced in thyroid cancers due to decreased NIS expression/function. As PI3K signaling is overactivated in many thyroid tumors, we investigated the effects of inhibitors for PI3K, Akt, or mTORC1 as well as their interplay on NIS modulation in thyroid cells under chronic TSH stimulation. PI3K inhibition by LY294002 increased NIS-mediated radioiodide uptake (RAIU) mainly through upregulation of NIS expression, however, mTORC1 inhibition by Rapamycin did not increase NIS-mediated RAIU despite increased NIS protein levels. In comparison, Akt inhibition by Akti-1/2 did not increase NIS protein levels, yet markedly increased NIS-mediated RAIU by decreasing iodide efflux rate and increasing iodide transport rate and iodide affinity of NIS. The effects of Akti-1/2 on NIS-mediated RAIU are not detected in nonthyroid cells, implying that Akti-1/2 or its derivatives may represent potential pharmacological reagents to selectively increase thyroidal radioiodine accumulation and therapeutic efficacy.

scholarly journals MEK signaling modulates sodium iodide symporter at multiple levels and in a paradoxical manner

2007 ◽  
Vol 14 (2) ◽  
pp. 421-432 ◽  
Author(s):  
Douangsone D Vadysirisack ◽  
Anjli Venkateswaran ◽  
Zhaoxia Zhang ◽  
Sissy M Jhiang
Keyword(s):  
Cell Surface ◽  
Atpase Activity ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Thyroid Cells ◽  
Thyroid Cancers ◽  
Protein Levels ◽  
Radioiodine Ablation

The Na+/I− symporter (NIS)-mediated iodide uptake is the basis for targeted radioiodine ablation of thyroid cancers. However, NIS-mediated radioiodide uptake (RAIU) activity is often reduced in thyroid cancers. As mitogen activated protein kinase (MAPK) signaling pathway is activated in about 70% of papillary thyroid carcinoma, we investigated whether MEK (MAPK kinase) inhibition will restore NIS protein levels and NIS-mediated RAIU activity in RET/PTC oncogene-transformed thyroid cells. We found that MEK inhibitor PD98059 increased NIS protein levels within 30 min of treatment. However, the increase of NIS protein level was not accompanied with an increase in NIS-mediated RAIU activity, particularly at early time points of PD98059 treatment. PD98059 also decreased RAIU activity mediated by exogenous NIS in non-thyroid cells. The transient decrease of RAIU activity by PD98059 in thyroid cells was not due to decreased NIS cell surface level, decreased NIS binding affinity for I− , or increased iodide efflux. While PD98059 moderately decreased Na+/K+-ATPase activity, ouabain titration indicates that the extent of decrease in Na+/K+-ATPase activity is much greater than the extent of decrease in RAIU activity. Additionally, a decrease of Na+/K+-ATPase activity was not accompanied with a decrease of biotin uptake activity mediated by Na+-dependent multivitamin transporter. Since PD98059 reduced Vmax− I− without decreasing NIS cell surface levels, it is most likely that PD98059 decreases the turnover rate of iodide transport with an yet to be identified mechanism.

scholarly journals Induction of follicle formation in long-term cultured normal human thyroid cells treated with thyrotropin stimulates iodide uptake but not sodium/iodide symporter messenger RNA and protein expression

2000 ◽  
Vol 167 (1) ◽  
pp. 125-135 ◽  
Author(s):  
T Kogai ◽  
F Curcio ◽  
S Hyman ◽  
EM Cornford ◽  
GA Brent ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Sodium Iodide ◽  
Human Thyroid ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Thyroid Cells ◽  
Protein Levels ◽  
Normal Human ◽  
Tsh Stimulation ◽  
Stimulation Of

Iodide uptake by the sodium/iodide symporter (NIS) in thyrocytes is essential for thyroid hormone production. Reduced NIS activity has been reported in thyroid diseases, including thyroid cancer and congenital hypothyroidism. The study of iodide uptake in thyrocytes has been limited by the availability of appropriate in vitro models. A new culture technique was recently developed that allows normal human thyroid primary culture cells to grow as monolayer cells and express differentiated functions for more than 3 months. We used this technique to study the effect of follicle formation and TSH on iodide uptake in these cells. Iodide uptake by the cells grown in monolayer was very low. Follicle formation was induced from monolayer cells, and electron micrographs demonstrated cell polarity in the follicles. No significant increase in iodide uptake was observed after TSH treatment of cells in monolayer or when follicle formation was induced without TSH. TSH stimulation of follicles, however, significantly increased iodide uptake ( approximately 4. 4-fold; P<0.001). Compared with iodide uptake in monolayers, the combination of follicle formation and TSH treatment stimulated iodide uptake synergistically to 12.0-fold (P<0.001). NIS messenger RNA (mRNA) and protein levels were almost the same in both monolayer cells and follicles. TSH treatment of monolayers and follicles produced significant (P<0.05) stimulation of mRNA ( approximately 4. 8- and approximately 4.3-fold respectively) and protein ( approximately 6.8- and 4.9-fold respectively). TSH stimulated NIS protein levels in both monolayer and follicles, however, stimulation of functional iodide uptake was only seen with TSH stimulation of follicles. The function of NIS may involve post-transcriptional events, such as intracellular sorting, membrane localization of NIS or another NIS regulatory factor. Polarized functions, such as iodide efflux into follicular lumina, may also contribute to the increased iodide concentration after follicle formation.

scholarly journals Forskolin, 8-Br-3′,5′-Cyclic Adenosine 5′-Monophosphate, and Catalytic Protein Kinase A Expression in the Nucleus Increase Radioiodide Uptake and Sodium/Iodide Symporter Protein Levels in RET/PTC1-Expressing Cells

2004 ◽  
Vol 89 (12) ◽  
pp. 6168-6172 ◽  
Author(s):  
Anjli Venkateswaran ◽  
Derek K. Marsee ◽  
Steven H. Green ◽  
Sissy M. Jhiang
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Sodium Iodide ◽  
Sodium Iodide Symporter ◽  
Thyroid Cells ◽  
Protein Levels ◽  
And Function ◽  
Kinase A

Abstract RET/PTC1, a thyroid-specific oncogene, has been reported to down-regulate sodium/iodide symporter (NIS) expression and function in vitro and in vivo. Recently, RET/PTC1 has been shown to interfere with TSH signaling at multiple levels in thyroid cells. The objective of this study was to investigate whether RET/PTC1-mediated NIS reduction can be rescued by activating cAMP-protein kinase A (PKA) pathways. We showed that both forskolin and 8-Br-cAMP increase radioiodide uptake and NIS protein in RET/PTC1-expressing cells to the same extent as the parental PC Cl 3 cells. We found that RET/PTC1 decreases nuclear localization of catalytic PKA, and forskolin treatment was able to counteract this RET/PTC1 effect. Furthermore, transient expression of catalytic PKA in the nucleus increased radioiodide uptake and NIS protein in RET/PTC1-expressing cells. Taken together, these studies suggest that RET/PTC1 down-regulates NIS expression by interrupting TSH/cAMP signaling, and this RET/PTC1 effect can be reversed by activating cAMP-PKA pathways.

scholarly journals The complex regulation of NIS expression and activity in thyroid and extrathyroidal tissues

2021 ◽  
Author(s):  
Garcilaso Riesco-Eizaguirre ◽  
Pilar Santisteban ◽  
Antonio De la Vieja
Keyword(s):  
Plasma Membrane ◽  
Regulatory Elements ◽  
Fine Tuning ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Transcriptional Regulatory Elements ◽  
Iodide Transport ◽  
Theranostic Agent ◽  
Transcriptional Regulatory ◽  
And Function

The sodium iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates active iodide transport into the thyroid gland and into several extrathyroidal tissues. NIS-mediated iodide uptake plays a pivotal role in the biosynthesis of thyroid hormones, of which iodide is an essential constituent. For 80 years radioiodide has been used for the diagnosis and treatment of thyroid cancer, a successful theranostic agent that is extending its use to extrathyroidal malignancies. The purpose of this review is to focus on the most recent findings regarding the mechanisms that regulate NIS both in thyroid and extra-thyroidal tissues. Among other issues, we discuss the different transcriptional regulatory elements that govern NIS transcription in different tissues, the epigenetic modifications that regulate its expression and the role that miRNAs play in fine tuning NIS after being transcribed. A review on the hormones, cytokines, and iodide itself that regulate NIS is provided. We also review the present stage of understanding NIS dysregulation in cancer, occupied mainly by convergent signaling pathways and by new insights in the route that NIS follows through different subcellular compartments to the plasma membrane. Furthermore, we cover NIS distribution and function in the increasing number of extrathyroidal tissues that express the symporter, as well as the role that NIS plays in tumor progression independently of its transport activity.

scholarly journals Expression and function of the novel proto-oncogene PBF in thyroid cancer: a new target for augmenting radioiodine uptake

2011 ◽  
Vol 210 (2) ◽  
pp. 157-163 ◽  
Author(s):  
Vicki E Smith ◽  
Jayne A Franklyn ◽  
Christopher J McCabe
Keyword(s):  
Thyroid Cancer ◽  
Current Data ◽  
Subcellular Localisation ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Radioiodine Uptake ◽  
Novel Target ◽  
And Function

Pituitary tumor-transforming gene (PTTG)-binding factor (PBF; PTTG1IP) was initially identified through its interaction with the human securin, PTTG. Like PTTG, PBF is upregulated in multiple endocrine tumours including thyroid cancer. PBF is believed to induce the translocation of PTTG into the cell nucleus where it can drive tumourigenesis via a number of different mechanisms. However, an independent transforming ability has been demonstrated both in vitro and in vivo, suggesting that PBF is itself a proto-oncogene. Studied in only a limited number of publications to date, PBF is emerging as a protein with a growing repertoire of roles. Recent data suggest that PBF possesses a complex multifunctionality in an increasing number of tumour settings. For example, PBF is upregulated by oestrogen and mediates oestrogen-stimulated cell invasion in breast cancer cells. In addition to a possible role in the induction of thyroid tumourigenesis, PBF overexpression in thyroid cancers inhibits iodide uptake. PBF has been shown to repress sodium iodide symporter (NIS) activity by transcriptional regulation of NIS expression through the human NIS upstream enhancer and further inhibits iodide uptake via a post-translational mechanism of NIS governing subcellular localisation. This review discusses the current data describing PBF expression and function in thyroid cancer and highlights PBF as a novel target for improving radioiodine uptake and thus prognosis in thyroid cancer.

scholarly journals Decreased Expression of Thyroglobulin and Sodium Iodide Symporter Genes in Hashimoto’s Thyroiditis

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Anna Popławska-Kita ◽  
Beata Telejko ◽  
Katarzyna Siewko ◽  
Maria Kościuszko-Zdrodowska ◽  
Natalia Wawrusewicz-Kurylonek ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Hashimoto’S Thyroiditis ◽  
Sodium Iodide ◽  
Interleukin 1 ◽  
Thyroid Volume ◽  
Needle Aspiration ◽  
Hashimoto's Thyroiditis ◽  
Sodium Iodide Symporter ◽  
Thyroid Cells ◽  
Iodide Transport

Aim. The aim of the study was to compare the expression of sodium iodide symporter (NIS), thyroglobulin (Tg), tumor necrosis factor-α(TNFα), and interleukin-1βgenes in patients with Hashimoto’s thyroiditis (HT) and healthy individuals.Subjects and Methods.Thyroid cells were obtained from 39 patients with HT and 15 controls by an ultrasound guided fine needle aspiration biopsy.Results. The patients with HT had lower Tg and NIS mRNA (P=0.002andP=0.001, resp.), as well as higher TNFαmRNA expression (P=0.049) than the controls. In the HT group Tg mRNA expression correlated positively with NIS mRNA expression (R=0.739,P=0.0001) and thyroid volume (R=0.465,P=0.0005), as well as negatively with TNFαmRNA expression (R=-0.490,P=0.001) and anti-peroxidase antibodies (TPOAb) level (R=-0.482,P=0.0002), whereas NIS mRNA expression correlated positively with thyroid volume (R=0.319,P=0.02), as well as negatively with TNFαmRNA expression (R=-0.529,P=0.0006) and TPOAb level (R=-0.422,P=0.001).Conclusions.Our results suggest that decreased Tg and NIS expression in thyroid cells may result in reduced active iodide transport and reduced thyroid volume in patients with HT.

scholarly journals Sodium/iodide symporter is expressed in the majority of seminomas and embryonal testicular carcinomas

2012 ◽  
Vol 216 (2) ◽  
pp. 125-133 ◽  
Author(s):  
S Micali ◽  
V Maggisano ◽  
A Cesinaro ◽  
M Celano ◽  
A Territo ◽  
...  
Keyword(s):  
Histone Deacetylase Inhibitors ◽  
Immunohistochemical Analysis ◽  
Testicular Tissue ◽  
Good Prognosis ◽  
Large Majority ◽  
Sodium Iodide Symporter ◽  
Testicular Tumors ◽  
Protein Levels ◽  
Iodide Transport ◽  
Testicular Carcinoma

Testicular cancer is the most frequent cancer in young men. The large majority of patients have a good prognosis, but in a small group of tumors, the current treatments are not effective. Radioiodine is routinely used in the treatment of thyroid cancer and is currently investigated as a potential therapeutic tool even for extra-thyroid tumors able to concentrate this radioisotope. Expression of Na+/I− symporter (NIS (SLC5A5)), the glycoprotein responsible for iodide transport, has been demonstrated in normal testicular tissue. In this study, we analyzed NIS expression in a large series of testicular carcinomas. Our retrospective series included 107 patients operated for testicular tumors: 98 typical seminomas, six embryonal carcinomas, one mixed embryonal choriocarcinoma, and two Leydig cells tumors. Expression and regulation of NIS mRNA and protein levels were also investigated in human embryonal testicular carcinoma cells (NTERA) by real-time RT-PCR and western blotting respectively. Immunohistochemical analysis showed the presence of NIS in the large majority of seminomas (90/98) and embryonal carcinomas (5/7) of the testis but not in Leydig cell carcinomas. Expression of NIS protein was significantly associated with lymphovascular invasion. In NTERA cells treated with the histone deacetylase inhibitors SAHA and valproic acid, a significant increase in NIS mRNA (about 60- and 30-fold vs control, P<0.001 and P<0.01 respectively) and protein levels, resulting in enhanced ability to uptake radioiodine, was observed. Finally, NIS expression in testicular tumors with the more aggressive behavior is of interest for the potential use of targeting NIS to deliver radioiodine in malignant cells.

scholarly journals Propylthiouracil increases sodium/iodide symporter gene expression and iodide uptake in rat thyroid cells in the absence of TSH

Thyroid ◽  
2012 ◽  
pp. 120521124804007
Author(s):  
Sue Mariko ◽  
Takeshi Akama ◽  
Akira Kawashima ◽  
Hannah Nakamura ◽  
Takeshi Hara ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sodium Iodide ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Thyroid Cells ◽  
Rat Thyroid

scholarly journals Cloning of the mouse sodium iodide symporter and its expression in the mammary gland and other tissues

2001 ◽  
Vol 170 (1) ◽  
pp. 185-196 ◽  
Author(s):  
B Perron ◽  
AM Rodriguez ◽  
G Leblanc ◽  
T Pourcher
Keyword(s):  
Mammary Gland ◽  
Mammalian Cells ◽  
Sodium Iodide ◽  
Distribution Analysis ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Reading Frame ◽  
Hormone Synthesis ◽  
Iodide Transport ◽  
Lactating Mammary Gland

Iodide concentration in milk by mammals is a necessary step for thyroid hormone synthesis by the newborn. With the purpose of using the mouse as an animal model to analyse the role of the sodium iodide symporter (NIS) in iodide transport and its regulation in the mammary gland, mouse NIS (mNIS) cDNA was isolated from lactating mice. The cloned sequence shows an open reading frame of 1854 nucleotides encoding a protein of 618 amino acids highly homologous to the rat and human NIS (95% and 81% identity respectively). Expression of mNIS in cultured mammalian cells induced cellular iodide accumulation. This iodide uptake process is sodium dependent and inhibited by thiocyanate and perchlorate. Tissue distribution analysis revealed that mNIS mRNAs are predominantly expressed in thyroid, stomach and in the lactating mammary gland and are present to a lower extent in several other tissues. Our data show for the first time that the level of mNIS mRNA is upregulated in the mammary gland during lactation.

scholarly journals Antagonistic effects of RAC1 and tumor-related RAC1b on NIS expression in thyroid

2019 ◽  
Vol 63 (4) ◽  
pp. 309-320
Author(s):  
Márcia Faria ◽  
Daniela Félix ◽  
Rita Domingues ◽  
Maria João Bugalho ◽  
Paulo Matos ◽  
...  
Keyword(s):  
Radioactive Iodine ◽  
Systemic Treatment ◽  
Survival Rates ◽  
Sodium Iodide Symporter ◽  
Iodide Uptake ◽  
Thyroid Cells ◽  
Rac1 Gtpase ◽  
First Time ◽  
Positive Effect

Thyroid cancer (TC) is the most common endocrine malignancy. The sodium–iodide symporter (NIS), responsible for active transport of iodide into thyroid cells, allows the use of radioactive iodine (RAI) as the systemic treatment of choice for TC metastatic disease. Still, patients with advanced forms of TC often lose the ability to respond to RAI therapy, which results in worse survival rates. We have shown that the overexpression of RAC1b, a tumor-related RAC1 splice variant, is associated with less favorable clinical outcomes in differentiated TCs derived from the follicular epithelial (DTCs). RAC1b overexpression is also significantly associated with the presence of MAPK-activating BRAFV600E mutation, which has been previously implicated in the loss of NIS expression. Here, we show that increased RAC1b levels are associated with NIS downregulation in DTCs and demonstrate that ectopic overexpression of RAC1b in non-transformed thyroid cells is sufficient to decrease TSH-induced NIS expression, antagonizing the positive effect of the canonically spliced RAC1 GTPase. Moreover, we clearly document for the first time in thyroid cells that both NIS expression and iodide uptake are hampered by RAC1 inhibition, highlighting the role of RAC1 in promoting TSH-induced NIS expression. Our findings support a role for RAC1 and RAC1b signaling in the regulation of NIS expression in thyroid cells and suggest that RAC1b in cooperation with other cancer-associated signaling cues may be implicated in the response of DTCs to RAI therapy.

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