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Tumor Biology

, Volume 37, Issue 5, pp 6275–6283 | Cite as

The small conductance calcium-activated potassium channel 3 (SK3) is a molecular target for Edelfosine to reduce the invasive potential of urothelial carcinoma cells

  • Konrad Steinestel
  • Stefan Eder
  • Konstantin Ehinger
  • Juliane Schneider
  • Felicitas Genze
  • Eva Winkler
  • Eva Wardelmann
  • Andres J. Schrader
  • Julie Steinestel
Original Article

Abstract

Metastasis is the survival-determining factor in urothelial carcinoma (UC) of the urinary bladder. The small conductance calcium-activated potassium channel 3 (SK3) enhances tumor cell invasion in breast cancer and malignant melanoma. Since Edelfosine, a glycerophospholipid with antitumoral properties, effectively inhibits SK3 channel activity, our goal was to evaluate SK3 as a potential molecular target to inhibit the gain of an invasive phenotype in UC. SK3 protein expression was analyzed in 208 tissue samples and UC cell lines. Effects of Edelfosine on SK3 expression and intracellular calcium levels as well as on cell morphology, cell survival and proliferation were assessed using immunoblotting, potentiometric fluorescence microscopy, and clonogenic/cell survival assay; furthermore, we analyzed the effect of Edelfosine and SK3 RNAi knockdown on tumor cell migration and invasion in vitro and in vivo. We found that SK3 is strongly expressed in muscle-invasive UC and in the RT112 cellular tumor model. Higher concentrations of Edelfosine have a strong antitumoral effect on UC cells, while 1 μM effectively inhibits migration/invasion of UC cells in vitro and in vivo comparable to the SK3 knockdown phenotype. Taken together, our results show strong expression of SK3 in muscle-invasive UC, consistent with the postulated role of the protein in tumor cell invasion. Edelfosine is able to effectively inhibit migration and invasion of UC cells in vitro and in vivo in an SK3-dependent way, pointing towards a possible role for Edelfosine as an antiinvasive drug to effectively inhibit UC cell invasion and metastasis.

Keywords

Urothelial carcinoma Small conductance calcium-activated potassium channel 3 Edelfosine Invasion Metastasis 

Notes

Acknowledgments

The authors would like to express their gratitude to Professor Axel Zander, Cellprotect & Co. KG (Eutin, Germany), for the kind gift of Edelfosine in pharmaceutical purity.

The work of KS is supported by the Deutsche Forschungsgemeinschaft (grant STE 2467/1-1) and by the Medical Faculty of the University of Münster (IMF grant I-SP111504).

Compliance with ethical standards

Conflict of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Konrad Steinestel
    • 1
  • Stefan Eder
    • 2
  • Konstantin Ehinger
    • 3
  • Juliane Schneider
    • 4
  • Felicitas Genze
    • 5
  • Eva Winkler
    • 5
  • Eva Wardelmann
    • 1
  • Andres J. Schrader
    • 6
  • Julie Steinestel
    • 6
  1. 1.Gerhard Domagk Institute of PathologyUniversity of MünsterMünsterGermany
  2. 2.Bundeswehr Institute of RadiobiologyMunichGermany
  3. 3.Department of General PhysiologyUniversity of UlmUlmGermany
  4. 4.Institute of Pathology and Molecular PathologyBundeswehrkrankenhaus UlmUlmGermany
  5. 5.Department of UrologyUlm University Medical CenterUlmGermany
  6. 6.Clinic of UrologyMünster University Medical CenterMünsterGermany

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