Retinoic acid modulation of thyroid dual oxidase activity in rats and its impact on thyroid iodine organification

The sodium–iodide symporter (NIS) mediates iodide uptake into the thyrocytes, which is important for the diagnosis and therapy of thyroid disorders. Decreased ability to uptake iodide in thyroid carcinomas reduces the efficacy of radioiodine therapy, and retinoic acid (RA) treatment reinduces iodide uptake. The effectiveness of treatment depends not only on iodide uptake but also on the ability of thyrocytes to organify iodine, which is catalyzed by thyroperoxidase (TPO) in the presence of H2O2. Our goal was to determine the influence of RA on thyroid iodide uptake, iodine organification, and TPO and dual oxidase (DuOx) activities. Normal rats were treated with all-trans-RA or 13-cis-RA (100 or 1500 μg/100 g body weight (b.w.), s.c.) for 14 and 28 days. The 2 h thyroid radioiodine content significantly decreased in rats treated with all-trans-RA (100 μg/100 g b.w.) for 14 days. In this group, NIS function and TPO activity were unchanged, whereas DuOx activity was significantly decreased, which might have contributed to the decrease in iodine organification. Both doses of 13-cis-RA for 28 days increased the 15 min thyroid radioiodine uptake, while the 2 h radioiodide uptake increased only in rats treated with the highest dose of 13-cis-RA. While TPO activity did not change, H2O2 generation was increased in this group, and serum thyroxine levels were normal. Since radioiodine half-life in the thyroid gland is important for treatment efficacy, our results highlight the importance of correctly choosing the RA isomer, the time and the dose of treatment, in order to improve the efficacy of radioiodine therapy.

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Retinoic Acid-Induced Stimulation of Sodium Iodide Symporter Expression and Cytotoxicity of Radioiodine in Prostate Cancer Cells

Endocrinology ◽

10.1210/en.2002-0206 ◽

2003 ◽

Vol 144 (8) ◽

pp. 3423-3432 ◽

Cited By ~ 12

Author(s):

C. Spitzweg ◽

I. V. Scholz ◽

E. R. Bergert ◽

D. J. Tindall ◽

C. Y. F. Young ◽

...

Keyword(s):

Prostate Cancer ◽

Retinoic Acid ◽

Cancer Cells ◽

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Prostate Cancer Cells ◽

Iodide Uptake ◽

Killing Effect ◽

Nis Gene

Abstract We reported recently the induction of androgen-dependent iodide uptake activity in the human prostatic adenocarcinoma cell line LNCaP using a prostate-specific antigen (PSA) promoter-directed expression of the sodium iodide symporter (NIS) gene. This offers the potential to treat prostate cancer with radioiodine. In the current study, we examined the regulation of PSA promoter-directed NIS expression and therapeutic effectiveness of 131I in LNCaP cells by all-trans-retinoic acid (atRA). For this purpose, NIS mRNA and protein expression levels in the NIS-transfected LNCaP cell line NP-1 were examined by Northern and Western blot analysis following incubation with atRA (10 −9 to 10−6m) in the presence of 10−9m mibolerone (mib). In addition, NIS functional activity was measured by iodide uptake assay, and in vitro cytotoxicity of 131I was examined by in vitro clonogenic assay. Following incubation with atRA, NIS mRNA levels in NP-1 cells were stimulated 3-fold in a concentration-dependent manner, whereas NIS protein levels increased 2.3-fold and iodide accumulation was stimulated 1.45-fold. This stimulatory effect of atRA, which has been shown to be retinoic acid receptor mediated, was completely blocked by the pure androgen receptor antagonist casodex (10−6m), indicating that it is androgen receptor dependent. The selective killing effect of 131I in NP-1 cells was 50% in NP-1 cells incubated with 10−9m mib. This was increased to 90% in NP-1 cells treated with atRA (10−7m) plus 10−9m mib. In conclusion, treatment with atRA increases NIS expression levels and selective killing effect of 131I in prostate cancer cells stably expressing NIS under the control of the PSA promoter. Therefore atRA may be used to enhance the therapeutic response to radioiodine in prostate cancer cells following PSA promoter-directed NIS gene delivery.

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Transcription Factor Nkx-2.5 Induces Sodium/Iodide Symporter Gene Expression and Participates in Retinoic Acid- and Lactation-Induced Transcription in Mammary Cells

Molecular and Cellular Biology ◽

10.1128/mcb.24.18.7863-7877.2004 ◽

2004 ◽

Vol 24 (18) ◽

pp. 7863-7877 ◽

Cited By ~ 36

Author(s):

Monica Dentice ◽

Cristina Luongo ◽

Antonia Elefante ◽

Romina Romino ◽

Raffaele Ambrosio ◽

...

Keyword(s):

Breast Cancer ◽

Transcription Factor ◽

Retinoic Acid ◽

Sodium Iodide ◽

Molecular Mechanisms ◽

Mammary Cells ◽

Sodium Iodide Symporter ◽

Iodide Uptake ◽

Potent Inducer ◽

Mcf 7

ABSTRACT The sodium/iodide symporter (NIS) is a plasma membrane protein that mediates active iodide transport in thyroid and mammary cells. It is a prerequisite for radioiodide treatment of thyroid cancer and a promising diagnostic and therapeutic tool for breast cancer. We investigated the molecular mechanisms governing NIS expression in mammary cells. Here we report that Nkx-2.5, a cardiac homeobox transcription factor that is also expressed in the thyroid primordium, is a potent inducer of the NIS promoter. By binding to two specific promoter sites (N2 and W), Nkx-2.5 induced the rNIS promoter (about 50-fold over the basal level). Interestingly, coincident with NIS expression, Nkx-2.5 mRNA and protein were present in lactating, but not virgin, mammary glands in two human breast cancer samples and in all-trans retinoic acid (tRA)-stimulated MCF-7 breast cancer cells. A cotransfected dominant-negative Nkx-2.5 mutant abolished tRA-induced endogenous NIS induction, which shows that Nkx-2.5 activity is critical for this process. Remarkably, in MCF-7 cells, Nkx-2.5 overexpression alone was sufficient to induce NIS and iodide uptake. In conclusion, Nkx-2.5 is a novel relevant transcriptional regulator of mammary NIS and could thus be exploited to manipulate NIS expression in breast cancer treatment strategies.

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Pharmacologically targeting a novel pathway of sodium iodide symporter trafficking to enhance radioiodine uptake

10.1101/622241 ◽

2019 ◽

Author(s):

Alice Fletcher ◽

Martin L. Read ◽

Caitlin E.M. Thornton ◽

Dean P. Larner ◽

Vikki L. Poole ◽

...

Keyword(s):

Sodium Iodide ◽

Disease Free Survival ◽

Sodium Iodide Symporter ◽

Iodide Uptake ◽

Radioiodine Uptake ◽

Proximity Ligation ◽

Central Protein ◽

Cell Surface Biotinylation ◽

Approved Drugs

ABSTRACTRadioiodine treatment fails ≥25% of patients with thyroid cancer and has been proposed as a potential treatment for breast cancer. Cellular iodide uptake is governed by the sodium iodide symporter (NIS), which is frequently mislocalized in thyroid and breast tumours. However, the trafficking of NIS to the plasma membrane (PM) is ill-defined. Through mass spectrometry, co-immunoprecipitation, cell surface biotinylation and proximity ligation assays we identify two proteins which control NIS subcellular trafficking: ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP). HiLo microscopy revealed ARF4 enhanced NIS trafficking in co-incident PM vesicles, governed by a C-terminal VXPX motif, whilst papillary thyroid cancers (PTC) demonstrate repressed ARF4 expression. In contrast, VCP, the central protein in ER-associated degradation, specifically bound NIS and decreased its PM localization. Five chemically distinct allosteric VCP inhibitors all overcame VCP-mediated repression of NIS function. In mice, two re-purposed FDA-approved VCP inhibitors significantly enhanced radioiodine uptake into thyrocytes, whilst human primary thyrocytes showed similar increases. Critically, PTC patients with high tumoural VCP expression who received radioiodine had strikingly worse disease-free survival. These studies now delineate the mechanisms of NIS trafficking, and for the first time open the therapeutic possibility of systemically enhancing radioiodine uptake in patients via FDA-approved drugs.One Sentence SummaryNovel NIS interactors ARF4 and VCP alter NIS trafficking in vitro, and FDA-approved VCP inhibitors can significantly enhance radioiodine uptake.

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Dexamethasone Stimulation of Retinoic Acid-Induced Sodium Iodide Symporter Expression and Cytotoxicity of 131-I in Breast Cancer Cells

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2005-0779 ◽

2006 ◽

Vol 91 (1) ◽

pp. 69-78 ◽

Cited By ~ 30

Author(s):

S. Unterholzner ◽

M. J. Willhauck ◽

N. Cengic ◽

M. Schütz ◽

B. Göke ◽

...

Keyword(s):

Breast Cancer ◽

Retinoic Acid ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Sodium Iodide ◽

Clonogenic Assay ◽

Sodium Iodide Symporter ◽

Iodide Uptake ◽

Mcf 7

Abstract Context: The sodium iodide symporter (NIS) mediates the active iodide uptake in the thyroid gland as well as lactating breast tissue. Recently induction of functional NIS expression was reported in the estrogen receptor-positive human breast cancer cell line MCF-7 by all-trans retinoic acid (atRA) treatment in vitro and in vivo, which might offer the potential to treat breast cancer with radioiodine. Objective: In the current study, we examined the effect of dexamethasone (Dex) on atRA-induced NIS expression and therapeutic efficacy of 131-I in MCF-7 cells. Design: For this purpose, NIS mRNA and protein expression levels in MCF-7 cells were examined by Northern and Western blot analysis after incubation with Dex (10−9 to 10−7m) in the presence of atRA (10−6m) as well as immunostaining using a mouse monoclonal human NIS-specific antibody. In addition, NIS functional activity was measured by iodide uptake and efflux assay, and in vitro cytotoxicity of 131-I was examined by in vitro clonogenic assay. Results: After incubation with Dex in the presence of atRA, NIS mRNA levels in MCF-7 cells were stimulated up to 11-fold in a concentration-dependent manner, whereas NIS protein levels increased up to 16-fold and iodide accumulation was stimulated up to 3- to 4-fold. Furthermore, iodide efflux was modestly decreased after stimulation with Dex in the presence of atRA. Furthermore, in the in vitro clonogenic assay, selective cytotoxicity of 131-I was significantly increased from approximately 17% in MCF-7 cells treated with atRA alone to 80% in MCF-7 cells treated with Dex in the presence of atRA. Conclusion: Treatment with Dex in the presence of atRA significantly increases functional NIS expression levels in addition to inhibiting iodide efflux, resulting in an enhanced selective killing effect of 131-I in MCF-7 breast cancer cells.

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Differential Regulation of Sodium/Iodide Symporter Gene Expression by Nuclear Receptor Ligands in MCF-7 Breast Cancer Cells

Endocrinology ◽

10.1210/en.2004-1334 ◽

2005 ◽

Vol 146 (7) ◽

pp. 3059-3069 ◽

Cited By ~ 37

Author(s):

Takahiko Kogai ◽

Yoko Kanamoto ◽

Andrew I. Li ◽

Lisa H. Che ◽

Emi Ohashi ◽

...

Keyword(s):

Breast Cancer ◽

Retinoic Acid ◽

Nuclear Receptor ◽

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Receptor Ligands ◽

Iodide Uptake ◽

Nuclear Receptor Ligands ◽

Mcf 7 ◽

Stimulation Of

Abstract The sodium/iodide symporter (NIS) mediates iodide uptake in lactating breast tissue and is expressed in some breast cancers. We have previously demonstrated that all-trans retinoic acid (tRA) stimulates NIS gene expression and the selective cytotoxic effect of β-emitting radioiodide-131 (131I) in both in vitro and in vivo MCF-7 breast cancer cell systems. We studied the ability of natural and synthetic retinoids, in combination with other nuclear receptor ligands, to achieve greater and more sustained induction of NIS in MCF-7 cells and enhance 131I-mediated cytotoxicity. Selective stimulation of retinoic acid receptor (RAR) β/γ produced marked NIS induction; and selective stimulation of RARα, RARγ, or retinoid X receptor produced more modest induction. Maximal NIS induction was seen with 9-cis retinoic acid and AGN190168, a RAR β/γ-agonist. Dexamethasone (Dex), but not the other nuclear receptor ligands, in combination with tRA synergistically induced iodide uptake and NIS mRNA expression, predominantly by prolonging NIS mRNA half-life. The addition of Dex reduced the EC50 of tRA for NIS stimulation to approximately 7%, such that 10 −7m tRA with addition of Dex enhanced iodide uptake and selective cytotoxicity of 131I greater than 10−6m tRA alone. AGN190168 combined with Dex synergistically increased iodide uptake and significantly prolonged induction (5 d) of iodide uptake compared with that induced by the combination of tRA/Dex or 9-cis retinoic acid/Dex. The addition of Dex reduced the effective dose of retinoid and prolonged the induction of NIS, especially with AGN190168, suggesting higher efficacy of 131I after combination treatment.

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Identification of novel sodium iodide symporter (NIS) interactors which modulate iodide uptake

Endocrine Abstracts ◽

10.1530/endoabs.44.oc3.4 ◽

2016 ◽

Author(s):

Alice Fletcher ◽

Vikki Poole ◽

Bhavika Modasia ◽

Waraporn Imruetaicharoenchoke ◽

Rebecca Thompson ◽

...

Keyword(s):

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Iodide Uptake

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Identification of novel sodium iodide symporter interactors which modulate iodide uptake

Endocrine Abstracts ◽

10.1530/endoabs.50.oc3.6 ◽

2017 ◽

Author(s):

Alice Fletcher ◽

Vikki Poole ◽

Bhavika Modasia ◽

Waraporn Imruetaicharoenchoke ◽

Rebecca Thompson ◽

...

Keyword(s):

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Iodide Uptake

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Identification of novel sodium iodide symporter (NIS) interactors which modulate radioiodine uptake

Endocrine Abstracts ◽

10.1530/endoabs.59.p224 ◽

2018 ◽

Author(s):

Alice Fletcher ◽

Vikki Poole ◽

Caitlin Thornton ◽

Kate Baker ◽

Rebecca Thompson ◽

...

Keyword(s):

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Radioiodine Uptake

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Rapid regulation of thyroid sodium–iodide symporter activity by thyrotrophin and iodine

Journal of Endocrinology ◽

10.1677/joe.1.05643 ◽

2005 ◽

Vol 184 (1) ◽

pp. 69-76 ◽

Cited By ~ 50

Author(s):

Andrea C F Ferreira ◽

Lívia P Lima ◽

Renata L Araújo ◽

Glaucia Müller ◽

Renata P Rocha ◽

...

Keyword(s):

Sodium Iodide ◽

Iodine Content ◽

Concomitant Administration ◽

High Serum ◽

Sodium Iodide Symporter ◽

Physiological Control ◽

Iodide Uptake ◽

Thyroid Hormone Biosynthesis ◽

Serum Tsh

Transport of iodide into thyrocytes, a fundamental step in thyroid hormone biosynthesis, depends on the presence of the sodium–iodide symporter (NIS). The importance of the NIS for diagnosis and treatment of diseases has raised several questions about its physiological control. The goal of this study was to evaluate the influence of thyroid iodine content on NIS regulation by thyrotrophin (TSH) in vivo. We showed that 15-min thyroid radioiodine uptake can be a reliable measurement of NIS activity in vivo. The effect of TSH on the NIS was evaluated in rats treated with 1-methyl-2-mercaptoimidazole (MMI; hypothyroid with high serum TSH concentrations) for 21 days, and after 1 (R1d), 2 (R2d), or 5 (R5d) days of withdrawal of MMI. NIS activity was significantly greater in both MMI and R1d rats. In R2d and R5d groups, thyroid iodide uptake returned to normal values, despite continuing high serum TSH, possibly as a result of the re-establishment of iodine organification after withdrawal of MMI. Excess iodine (0.05% NaI for 6 days) promoted a significant reduction in thyroid radioiodide uptake, an effect that was blocked by concomitant administration of MMI, confirming previous findings that iodine organification is essential for the iodide transport blockade seen during iodine overload. Therefore, our data show that modulation of the thyroid NIS by TSH depends primarily on thyroid iodine content and, further, that the regulation of NIS activity is rapid.

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