KT5823 Differentially Modulates Sodium Iodide Symporter Expression, Activity, and Glycosylation between Thyroid and Breast Cancer Cells

Beyer, Sasha; Lakshmanan, Aparna; Liu, Yuyu; Zhang, Xiaoli; Wapnir, Irene; Smolenski, Albert; Jhiang, Sissy

doi:10.1210/en.2010-0782

Cited by 20 publications

(16 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We choose tRA/H-treated MCF-7 cells to investigate the effect of overexpression of miR-339-5p on the levels of endogenous h NIS mRNA and hNIS-mediated RAIU, as it is well established that tRA/H significantly induces the expression and function of hNIS in MCF-7 cells (Kogai et al . 2000, Beyer et al . 2011).…”

Section: Resultsmentioning

confidence: 99%

microRNA-339-5p modulates Na+/I− symporter-mediated radioiodide uptake

Lakshmanan¹,

Wójcicka²,

Kotlarek³

et al. 2014

Endocrine-Related Cancer

Self Cite

View full text Add to dashboard Cite

Na+/I− symporter (NIS)-mediated radioiodide uptake (RAIU) serves as the basis for targeted ablation of thyroid cancer remnants. However, many patients with thyroid cancer have reduced NIS expression/function and hence do not benefit from radioiodine therapy. microRNA (miR) has emerged as a promising therapeutic target in many diseases; yet, the role of miRs in NIS-mediated RAIU has not been investigated. In silico analysis was used to identify miRs that may bind to the 3′UTR of human NIS (hNIS). The top candidate miR-339-5p directly bound to the 3′UTR of hNIS. miR-339-5p overexpression decreased NIS-mediated RAIU in HEK293 cells expressing exogenous hNIS, decreased the levels of NIS mRNA, and RAIU in transretinoic acid/hydrocortisone (tRA/H)-treated MCF-7 human breast cancer cells as well as thyrotropinstimulated PCCl3 rat thyroid cells. Nanostring nCounter rat miR expression assay was conducted to identify miRs deregulated by TGFβ, Akti-1/2, or 17-AAG known to modulate RAIU in PCCl3 cells. Among 38miRs identified, 18 were conserved in humans. One of the 18 miRs, miR-195, was predicted to bind to the 3′ UTR of hNIS and its overexpression decreased RAIU in tRA/H-treated MCF-7 cells. miR-339-5p was modestly increased inmost papillary thyroid carcinomas (PTCs), yet miR-195 was significantly decreased in PTCs. Interestingly, the expression profiles of 18 miRs could be used to distinguish most PTCs from nonmalignant thyroid tissues. This is the first report, to our knowledge, demonstrating that hNIS-mediated RAIU can be modulated by miRs, and that the same miRs may also play roles in the development or maintenance of thyroid malignancy. Accordingly, miRs may serve as emerging targets to halt the progression of thyroid cancer and to enhance the efficacy of radioiodine therapy.

show abstract

Section: Resultsmentioning

confidence: 99%

microRNA-339-5p modulates Na+/I− symporter-mediated radioiodide uptake

Lakshmanan¹,

Wójcicka²,

Kotlarek³

et al. 2014

Endocrine-Related Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…The lower molecular mass of hypoglycosylated NIS suggests that KT5823 has a similar effect on glycosylation to brefeldin A, an inhibitor of protein transport from the ER to the Golgi apparatus. The effect of decreased iodide uptake in experimental KT5823-treated breast cancer cell mutants with single or triple mutations of NIS glycosylation sites (N225Q, N489Q, N502Q, N225Q/N489Q/N502Q) showed that the inhibition of iodide uptake was only partly connected with hypoglycosylation of NIS [ 84 ].…”

Section: Glycosylation Of Proteins Involved In Thyroid Functioningmentioning

confidence: 99%

Glycosylation in the Thyroid Gland: Vital Aspects of Glycoprotein Function in Thyrocyte Physiology and Thyroid Disorders

Ząbczyńska

Kozłowska

Pocheć

2018

IJMS

View full text Add to dashboard Cite

The key proteins responsible for hormone synthesis in the thyroid are glycosylated. Oligosaccharides strongly affect the function of glycosylated proteins. Both thyroid-stimulating hormone (TSH) secreted by the pituitary gland and TSH receptors on the surface of thyrocytes contain N-glycans, which are crucial to their proper activity. Thyroglobulin (Tg), the protein backbone for synthesis of thyroid hormones, is a heavily N-glycosylated protein, containing 20 putative N-glycosylated sites. N-oligosaccharides play a role in Tg transport into the follicular lumen, where thyroid hormones are produced, and into thyrocytes, where hyposialylated Tg is degraded. N-glycans of the cell membrane transporters sodium/iodide symporter and pendrin are necessary for iodide transport. Some changes in glycosylation result in abnormal activity of the thyroid and alteration of the metabolic clearance rate of hormones. Alteration of glycan structures is a pathological process related to the progression of chronic diseases such as thyroid cancers and autoimmunity. Thyroid carcinogenesis is accompanied by changes in sialylation and fucosylation, β1,6-branching of glycans, the content and structure of poly-LacNAc chains, as well as O-GlcNAcylation, while in thyroid autoimmunity the main processes affected are sialylation and fucosylation. The glycobiology of the thyroid gland is an intensively studied field of research, providing new data helpful in understanding the role of the sugar component in thyroid protein biology and disorders.

show abstract

“…Membrane protein is generally produced in the endoplasmic reticulum, and then move to cellular membrane through the golgi complex. This membrane localization process requires proper protein post-translational modification including phosphorylation and glycosylation [ 16 , 17 ]. Levi et al .…”

Section: Introductionmentioning

confidence: 99%

Glycosylation of Sodium/Iodide Symporter (NIS) Regulates Its Membrane Translocation and Radioiodine Uptake

et al. 2015

View full text Add to dashboard Cite

PurposeHuman sodium/iodide symporter (hNIS) protein is a membrane glycoprotein that transports iodide ions into thyroid cells. The function of this membrane protein is closely regulated by post-translational glycosylation. In this study, we measured glycosylation-mediated changes in subcellular location of hNIS and its function of iodine uptake.MethodsHeLa cells were stably transfected with hNIS/tdTomato fusion gene in order to monitor the expression of hNIS. Cellular localization of hNIS was visualized by confocal microscopy of the red fluorescence of tdTomato. The expression of hNIS was evaluated by RT-PCR and immunoblot analysis. Functional activity of hNIS was estimated by radioiodine uptake. Cyclic AMP (cAMP) and tunicamycin were used to stimulate and inhibit glycosylation, respectively. In vivo images were obtained using a Maestro fluorescence imaging system.ResultscAMP-mediated Glycosylation of NIS resulted in increased expression of hNIS, stimulating membrane translocation, and enhanced radioiodine uptake. In contrast, inhibition of glycosylation by treatment with tunicamycin dramatically reduced membrane translocation of intracellular hNIS, resulting in reduced radioiodine uptake. In addition, our hNIS/tdTomato fusion reporter successfully visualized cAMP-induced hNIS expression in xenografted tumors from mouse model.ConclusionsThese findings clearly reveal that the membrane localization of hNIS and its function of iodine uptake are glycosylation-dependent, as our results highlight enhancement of NIS expression and glycosylation with subsequent membrane localization after cAMP treatment. Therefore, enhancing functional NIS by the increasing level of glycosylation may be suggested as a promising therapeutic strategy for cancer patients who show refractory response to conventional radioiodine treatment.

show abstract

KT5823 Differentially Modulates Sodium Iodide Symporter Expression, Activity, and Glycosylation between Thyroid and Breast Cancer Cells

Cited by 20 publications

References 38 publications

microRNA-339-5p modulates Na+/I− symporter-mediated radioiodide uptake

microRNA-339-5p modulates Na+/I− symporter-mediated radioiodide uptake

Glycosylation in the Thyroid Gland: Vital Aspects of Glycoprotein Function in Thyrocyte Physiology and Thyroid Disorders

Glycosylation of Sodium/Iodide Symporter (NIS) Regulates Its Membrane Translocation and Radioiodine Uptake

Contact Info

Product

Resources

About