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Specific block of androgen receptor activity by antisense oligonucleotides

Prostate Cancer and Prostatic Diseases volume 6, pages 27–33 (2003)Cite this article

Abstract

Claims about molecular mechanisms underlying the resistance to anti-hormones of prostate cancer cells find support in biological experiments, which involve hormone-independent activation of the androgen receptor's (AR) transcriptional activity. In order to test this hypothesis, we attempted to shut down the expression of AR by the means of target-directed antisense oligonucleotides. A set of 49 oligonucleotides matching sequences of the AR mRNA either in the coding sequence or in the 3′ and 5′ untranslated regions were synthesized and examined in a cellular AR-dependent reporter system. Five antisense oligonucleotides were identified as highly potent inhibitors of AR-driven gene expression in a cellular reporter assay. These five were further profiled using point-mutated control sequences for the assessment of AR inhibition. In addition the expression of another AR-driven gene, the modulator of PSA expression (gene for inhibition of prostate specific antigen, an endogenous, AR-driven gene) was examined. Finally, we observed that the hormone-independent but AR-mediated transactivation by IGF-1 could also be specifically shut-down by these antisense oligonucleotides. The selection of highly target-restricted antisense oligonucleotides in the prostate cancer cell line LNCaP provided tools to study a central role of the androgen receptor in growth regulation of prostatic cancer cell lines and could be of utility in cancer situations in vivo.

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Acknowledgements

We would like to express our thanks to Bernard Cuenoud and Jan Weiler for their technological expertise and for stimulating discussion, and Geneviève Albrecht for excellent technical assistance!

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Authors and Affiliations

  1. Oncology Department, Novartis AG, Pharma Research, Basel, Switzerland

    F Hamy, V Brondani, R Spoerri, S Rigo & C Stamm

  2. Institute for Medical Microbiology, University of Basel, Basel, Switzerland

    F Hamy & T Klimkait

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  1. F Hamy
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  2. V Brondani
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  3. R Spoerri
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  4. S Rigo
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  5. C Stamm
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  6. T Klimkait
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Correspondence to F Hamy.

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Hamy, F., Brondani, V., Spoerri, R. et al. Specific block of androgen receptor activity by antisense oligonucleotides. Prostate Cancer Prostatic Dis 6, 27–33 (2003). https://doi.org/10.1038/sj.pcan.4500603

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