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Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines

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Summary

Androgens play an important role in controlling the growth of the normal prostate gland and in the pathogenesis of benign prostate hyperplasia, and prostate cancer. Although testosterone is the main androgen secreted from the testes, dihydrotestosterone (DHT), a more potent androgen converted from testosterone by 5α-reductase isozymes, type I and II, is the major androgen in the prostate cells. The aim of this study is to investigate the cellular and molecular effects of dutasteride, a potent inhibitor of 5α-reductase type I and type II, in androgen-responsive (LNCaP) and androgen-unresponsive (DU145) human prostate cancer(PCa) cell lines. The expression pattern of 190 genes, selected on the basis of their proved or potential role in prostate cancerogenesis related to androgen signalling, were analysed using a low density home-made oligoarray (AndroChip 2). Our results show that dutasteride reduces cell viability and cell proliferation in both cell lines tested. AndroChip 2 gene signature identified in LNCaP a total of 11 genes differentially expressed (FC ≥ ±1.5). Eight of these genes, were overexpressed and three were underexpressed. Overexpressed genes included genes encoding for proteins involved in biosynthesis and metabolism of androgen (HSD17B1;HSD17B3;CYP11B2), androgen receptor and androgen receptor co-regulators (AR;CCND1), and signal transduction(ERBB2; V-CAM; SOS1) whereas, underexpressed genes (KLK3; KLK2; DHCR24) were androgen-regulated genes (ARGs). No differentially expressed genes were scored in DU145. Microarray data were confirmed by quantitative real-time PCR assay (QRT-PCR). These data offer a selective genomic signature for dutasteride treatment in prostate epithelial cells and provide important insights in prostate cancer pathophysiology.

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Acknowledgements

We thank GlaxoSmithKline for providing us the dutasteride drug and Dr. Roger Rittmaster for the useful comments. This work was in part supported by funds from AIRC (Associazione Italiana per la Ricerca sul Cancro) Regional Grant to G.N.

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Authors and Affiliations

  1. Department of Biopathology and Diagnostic Imaging, Tor Vergata University, Via Montpellier 1, 00133, Rome, Italy

    Michela Biancolella, Daniela Minella, Lucia Vecchione, Franca D’Amico & Giuseppe Novelli

  2. Department of Internal Medicine-PTV, Tor Vergata University, Rome, Italy

    Alessandra Valentini, Paolo Gravina, Giorgio Federici & Sergio Bernardini

  3. CASPUR, Rome, Italy

    Giovanni Chillemi & Susana Bueno

  4. Department of Biology, Tor Vergata University, Rome, Italy

    Gianluca Prosperini & Alessandro Desideri

Authors
  1. Michela Biancolella
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  2. Alessandra Valentini
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  4. Lucia Vecchione
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  5. Franca D’Amico
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  13. Giuseppe Novelli
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Correspondence to Giuseppe Novelli.

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Supplementary Information is linked to web site http://www.geneticaumana.net/ricerca_news_scheda.php?id=53

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Biancolella, M., Valentini, A., Minella, D. et al. Effects of dutasteride on the expression of genes related to androgen metabolism and related pathway in human prostate cancer cell lines. Invest New Drugs 25, 491–497 (2007). https://doi.org/10.1007/s10637-007-9070-7

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  • DOI: https://doi.org/10.1007/s10637-007-9070-7

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