Activation of the PI3 Kinase Pathway By Retinoic Acid Mediates Sodium/Iodide Symporter Induction and Iodine Transport in MCF-7 Breat Cancer Cells

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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Sutherlandia frutescens treatment induces apoptosis and modulates the PI3-kinase pathway in colon cancer cells

South African Journal of Botany ◽

10.1016/j.sajb.2015.04.013 ◽

2015 ◽

Vol 100 ◽

pp. 20-26 ◽

Cited By ~ 6

Author(s):

G. Leisching ◽

B. Loos ◽

T. Nell ◽

A.-M. Engelbrecht

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Pi3 Kinase ◽

Colon Cancer Cells ◽

Pi3 Kinase Pathway ◽

Kinase Pathway ◽

Sutherlandia Frutescens

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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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Stimulation of retinoic acid-induced functional sodium iodide symporter (NIS) expression and cytotoxicity of 131I by carbamazepine in breast cancer cells

Breast Cancer Research and Treatment ◽

10.1007/s10549-010-0835-x ◽

2010 ◽

Vol 125 (2) ◽

pp. 377-386 ◽

Cited By ~ 9

Author(s):

Michael J. Willhauck ◽

Dennis J. O`Kane ◽

Nathalie Wunderlich ◽

Burkhard Göke ◽

Christine Spitzweg

Keyword(s):

Breast Cancer ◽

Retinoic Acid ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Sodium Iodide ◽

Sodium Iodide Symporter ◽

Stimulation Of

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Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.140217197 ◽

2000 ◽

Vol 97 (15) ◽

pp. 8519-8524 ◽

Cited By ~ 93

Author(s):

T. Kogai ◽

J. J. Schultz ◽

L. S. Johnson ◽

M. Huang ◽

G. A. Brent

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Retinoic Acid ◽

Cell Line ◽

Breast Cancer Cell ◽

Breast Cancer Cell Line ◽

Sodium Iodide ◽

Cancer Cell Line ◽

Sodium Iodide Symporter ◽

Mcf 7

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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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