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  • Oncogenomics
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KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer

Oncogene volume 26, pages 2525–2534 (2007)Cite this article

Abstract

Molecular mechanisms of prostate cancer progression are poorly understood. Here, we studied gene amplification of the large conductance calcium-activated potassium channel alpha subunit (KCNMA1), which is located at the chromosomal region 10q22. Fluorescence in situ hybridization (FISH) revealed KCNMA1 amplification in 16% of 119 late-stage human prostate cancers and in the hormone-insensitive prostate cancer cell line PC-3. In contrast, KCNMA1 amplification was absent in 33 benign controls, 32 precursor lesions and in 105 clinically organ-confined prostate cancers. Amplification was associated with mRNA and protein overexpression as well as increased density of BK channel protein and β-estradiol-insensitive BK currents in PC-3 cells as compared to non-amplified control cell lines. Specific blockade of BK channels by iberiotoxin or RNAi significantly inhibited K+ currents and growth of PC-3 cells. The data demonstrate that 10q22 amplification drives KCNMA1 expression and cell proliferation. Thus, KCNMA1 qualifies as a promising diagnostic and therapeutic target in patients with prostate cancer.

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Acknowledgements

We are grateful to Martina Mirlacher, Alex Rufle Hedvika Novotny, Ursula Dürrmüller and Dr Heide Tullberg from the Institute for Pathology, University Hospital Basel, and Dr Rainer Schreiber, Professor Dr Richard Warth and Melanie Spitzner at the University of Regensburg for their expert technical advice. We also thank Professor Dr Peter Ruth, Dr Matthias Sausbier and Ulrike Sausbier from the Institute of Pharmacy, University of Tübingen, Germany for generously providing the BK channel antibody.

The PC-3 cell line was kindly provided by Spyro Mousses, PhD (Translational Genomics Research Institute, Gaithersburg, MD, USA), LNCaP was from Meera Srivastava, PhD (Uniformed Services University of the Health Sciences, Bethesda, MD, USA) and BPH-1 was from Holger Rumpold, MD (Institute for Biomedical Ageing, Innsbruck, Austria).

This study was supported by the Stammbach Foundation/SWISS BRIDGE (KLS 01114-02-2001), by the Swiss National Science Foundation (Grant No. 3100A0-105413) and by the Deutsche Forschungsgemeinschaft DFG SCHR 752/2-1.

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  1. R Simon

    Present address: Department of Pathology, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany

  2. P Schraml

    Present address: Institute for Surgical Pathology, University Hospital Zurich, CH-8091, Zurich, Switzerland

  3. K Kunzelmann and L Bubendorf: These authors share senior authorship.

Authors and Affiliations

  1. Institute for Pathology, University Hospital Basel, Basel, Switzerland

    M Bloch, R Simon, P Schraml, M J Mihatsch & L Bubendorf

  2. Department of Physiology, University of Regensburg, Regensburg, Germany

    J Ousingsawat & K Kunzelmann

  3. Department of Urology, University of Basel, Liestal, Switzerland

    T C Gasser

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Correspondence to L Bubendorf.

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Bloch, M., Ousingsawat, J., Simon, R. et al. KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer. Oncogene 26, 2525–2534 (2007). https://doi.org/10.1038/sj.onc.1210036

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