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Mediated Iodide Transport in Breast Cancer Cells Hydrocortisone And Hydrocortisone and Purinergic Signaling Stimulate Sodium/Iodide Symporter (NIS)-Mediated Iodide Transport in Breast Cancer Cells Orsolya Dohán, Antonio De la Vieja and Nancy Carrasco Mol. Endocrinol. 2006 20:1121-1137 originally published online Jan 26, 2006; , doi: 10.1210/me.2005-0376 To subscribe to Molecular Endocrinology or any of the other journals published by The Endocrine Society please go to: http://mend.endojournals.org//subscriptions/ Copyright © The Endocrine Society. All rights reserved. Print ISSN: 0021-972X. Online 0888-8809/06/$15.00/0 Molecular Endocrinology 20(5):1121–1137 Printed in U.S.A. Copyright © 2006 by The Endocrine Society doi: 10.1210/me.2005-0376 Hydrocortisone and Purinergic Signaling Stimulate Sodium/Iodide Symporter (NIS)-Mediated Iodide Transport in Breast Cancer Cells Orsolya Doha´n, Antonio De la Vieja, and Nancy Carrasco Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461 The sodium/iodide symporter (NIS) mediates a re- pression and plasma membrane targeting in markably effective targeted radioiodide therapy in MCF-7 cells, leading to at least a 100% increase in thyroid cancer; this approach is an emerging can- iodide uptake. Surprisingly, the adenyl cyclase ac- didate for treating other cancers that express NIS, tivator forskolin, which promotes NIS expression in whether endogenously or by exogenous gene thyroid cells, markedly decreases tRa-induced NIS transfer. Thus far, the only extrathyroidal malig- protein expression in MCF-7 cells. Isobutylmethyl- nancy known to express functional NIS endog- xanthine increases tRa-induced NIS expression in enously is breast cancer. Therapeutic efficacy in MCF-7 cells, probably through a purinergic signal- thyroid cancer requires that radioiodide uptake be ing system independent of isobutylmethylxanthine’s maximized in tumor cells by manipulating well- action as a phosphodiesterase inhibitor. We also known regulatory factors of NIS expression in thy- observed that neither iodide, which at high con- roid cells, such as TSH, which stimulates NIS ex- centrations down-regulates NIS in the thyroid, nor pression via cAMP. Similarly, therapeutic efficacy cAMP has a significant effect on NIS expression in breast cancer will likely depend on manipulating in MCF-7 cells. Our findings may open new strat- NIS regulation in mammary cells, which differs egies for breast-selective pharmacological mod- from that in the thyroid. Human breast adenocar- ulation of functional NIS expression, thus im- cinoma MCF-7 cells modestly express endogenous proving the feasibility of using radioiodide to NIS when treated with all-trans-retinoic acid (tRa). effectively treat breast cancer. (Molecular Endo- We report here that hydrocortisone and ATP each crinology 20: 1121–1137, 2006) markedly stimulates tRa-induced NIS protein ex- MAJOR DRAWBACK OF available traditional substrates of transport proteins that are selectively Acytotoxic anticancer therapies is that they are sig- expressed in tumoral tissue. These transport proteins nificantly toxic to normal cells as well. Therefore, the then translocate the radionuclides into tumoral cells ultimate aim of any new anticancer therapy is to only. achieve selective destruction of cancerous tissue with The prime example of targeted radiation therapy via minimal harm to healthy cells. One of the most prom- a selectively expressed plasma membrane transporter ising approaches to accomplishing this goal is tar- is radioiodide therapy. This is the most effective anti- geted radiation therapy. In recent years, radionuclide- cancer targeted radiotherapy available today (2) and bearing monoclonal antibodies (mAbs) have been has been employed for more than 60 yr to destroy approved by the United States Federal Drug Admin- thyroid cancer remnants and/or metastases after thy- istration, and several other antibodies (Abs) are cur- roidectomy (3). The presence of the sodium/iodide rently on clinical trials. These mAbs bind to tumor- symporter (NIS) in thyroid cancer cells ensures that specific antigens, thus selectively targeting cytotoxic administered radioiodide is selectively accumulated in radionuclides to the tumor (1). Alternatively, cytotoxic these cells, causing little damage to other cells and radionuclides can be specifically targeted by acting as only minimal side effects (2). Thus far, radioiodide therapy has been viewed as applicable only to thyroid First Published Online January 26, 2006 cancer. Nevertheless, recent observations have raised Abbreviations: Abs, Antibodies; 8-Br-cAMP, 8-bromo- cAMP; FACS, fluorescence-activated cell sorting; HBSS, the possibility of applying radioiodide therapy to Hank’s balanced salt solution; IBMX, isobuthylmethylxantine; breast cancer (4–6), and potentially to other cancers as mAbs, monoclonal antibodies; NIS, sodium/iodide sym- well, by introducing NIS into the tumor via viral vectors porter; NUE, NIS upstream enhancer; PBS-C-M, PBS con- (7–9) or up-regulating the tumors’ endogenous NIS taining 0.1 mM CaCl and1mM MgCl ; tRA, all-trans-retinoic 2 2 expression, if present (2, 4, 10, 11). acid; tRAH, hydrocortisone combined with tRA. NIS was cloned in 1996 in our laboratory from the Molecular Endocrinology is published monthly by The Endocrine Society (http://www.endo-society.org), the highly functional rat thyroid-derived FRTL-5 cells (12). foremost professional society serving the endocrine It was subsequently demonstrated that the same NIS community. protein mediates IϪ transport in all tissues that con- 1121 1122 Mol Endocrinol, May 2006, 20(5):1121–1137 Doha´n et al. • Regulation of NIS-Mediated Iodide Uptake Fig. 1. Hydrocortisone Increases tRa-induced Functional NIS Expression in MCF-7 Cells Ϫ A, Steady-state I uptake in MCF-7 cells: nontreated (white bar); treated for 48 h with 10 ␮M hydrocortisone (H) (spotted bar), 1 ␮M tRa (diagonally striped bar), or tRa and H combined (horizontally striped bar). Cells were incubated for 30 min with 20 ␮M Na125I and assayed as described in Materials and Methods. For comparison, IϪ uptake in FRTL-5 cells is shown (gray bar). Black ␮ Ϫ Ϫ bars represent NaClO4 (40 M) inhibition of I uptake in all cases. B, I efflux in MCF-7 cells treated with either tRa or tRaH is Ϫ similar and significantly slower than in FRTL-5 cells. Cells were incubated with 20 ␮M Na125I for 30 min and washed; I efflux was measured by replacing the HBSS solution every 10 min for 3 h and quantitating 125I. f, tRa-treated MCF-7 cells; F, tRaH-treated ‚ Ϫ MCF-7 cells; , FRTL-5 cells. C and D, Hydrocortisone increases the Vmax of NIS-mediated I transport in tRa-treated MCF-7 Ϫ ϩ Ϫ cells without changing the Km of the transporter for either I (panel C) or Na (panel D). Initial rates (2-min time points) of I uptake were determined at the indicated concentrations of IϪ (as described in Materials and Methods). Calculated curves were generated Doha´n et al. • Regulation of NIS-Mediated Iodide Uptake Mol Endocrinol, May 2006, 20(5):1121–1137 1123 centrate IϪ, including salivary glands, gastric mucosa, therapeutic efficiency, patients with metastatic thyroid and lactating mammary gland (4, 13, 14). Interestingly, disease are given a low iodide diet and recombinant NIS is regulated differently in each of these tissues (4, TSH (22). This greatly increases functional NIS expres- 14, 15). Our secondary structure model for NIS pre- sion and radioiodide accumulation in malignant thy- dicts 13 transmembrane segments (16); we have ex- roid tissue. Similarly, it is imperative to find compara- perimentally demonstrated that the amino terminus ble ways to selectively induce or increase existing faces extracellularly and the carboxy terminus faces endogenous functional NIS expression in breast can- intracellularly (17). cer. Kogai et al. (11) have reported the induction of Driven by the Naϩ gradient generated by the functional NIS expression by all-trans-retinoic acid Naϩ/Kϩ ATPase, NIS couples the inward downhill (tRa) in the human adenocarcinoma-derived MCF-7 transport of Naϩ down its concentration gradient to cell line. MCF-7 cells are an excellent and widely used the inward uphill translocation of IϪ against its elec- in vitro system for studying NIS regulation in human trochemical gradient. NIS transports 2 Naϩ per each breast cancer cells. Here we analyzed the effects of IϪ (18). Importantly, in addition to radioiodide, NIS also hormones and other factors on NIS expression in transports other radionuclides with high therapeutic MCF-7 cells. We found that glucocorticoids and puri- 188 211 potential, such as ReO4 (19) and At (20). nergic regulatory mechanisms greatly enhanced tRa- We have demonstrated in healthy mammary tissue induced functional NIS expression in MCF-7 cells. In- that NIS is expressed in lactating but not in nonlactat- terestingly, factors that increased NIS expression in ing breast and have shown that NIS expression is MCF-7 cells have the opposite effect in FRTL-5 cells, regulated by lactogenic hormones (4). By comparison, i.e. they down-regulate NIS expression. Our findings in the thyroid NIS is expressed continuously and is open new strategies for carrying out selective phar- primarily regulated by TSH (14, 15, 17). We have ob- macological modulation of radioiodide uptake in served NIS-mediated IϪ uptake in mammary adeno- breast cancer. carcinomas in transgenic mice bearing ras or neu on- cogenes and, even more significantly, we found NIS expression in more than 80% of human breast cancers RESULTS by immunohistochemistry (4, 6, 21), whereas there was no NIS expression in the surrounding noncancer- Hydrocortisone Increases tRa-Induced Iodide ous breast tissue. In short, some regulatory mecha- Uptake in MCF-7 Cells nisms cause NIS to be expressed only in lactating breast and breast cancer but not in noncancerous The combination of insulin, prolactin, and hydrocorti- nonlactating breast. Furthermore, we have recently sone induces the synthesis of milk proteins such as demonstrated in vivo that NIS-mediated IϪ uptake oc- caseins and whey proteins in mammary epithelial cells curs in human breast cancer metastases, and that in vitro (23–25).
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