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

Department of Internal Medicine II (C.S., I.V.S., B.G.), Klinikum Grosshadern, Ludwig-Maximilians-University, Munich 81377, Germany; and Departments of Endocrinology (E.R.B., J.C.M.) and Urology (D.J.T., C.Y.F.Y.), Mayo Clinic, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Christine Spitzweg, M.D., Klinikum Grosshadern, Medizinische Klinik II, Marchioninistrasse 15, 81377 Muenchen, Germany. E-mail: spitzweg.christine{at}gmx.net.

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^-6 M) in the presence of 10^-9 M 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^-6 M), 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^-9 M mib. This was increased to 90% in NP-1 cells treated with atRA (10^-7 M) plus 10^-9 M 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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