title: The small conductance calcium-activated potassium channel 3 (SK3) is a molecular target for Edelfosine to reduce the invasive potential of urothelial carcinoma cells.
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.
authors.affiliation: Gerhard Domagk Institute of Pathology, University of Münster, Domagkstrasse 17, 48149, Münster, Germany. konrad@steinestel.com.
authors.forename: Konrad
authors.initials: K
authors.lastname: Steinestel
authors.affiliation: Bundeswehr Institute of Radiobiology, Neuherbergstr. 11, 80937, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Eder
authors.affiliation: Department of General Physiology, University of Ulm, Albert-Einstein-Allee 11, 89081, Ulm, Germany.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Ehinger
authors.affiliation: Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Oberer Eselsberg 40, 89081, Ulm, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Schneider
authors.affiliation: Department of Urology, Ulm University Medical Center, Prittwitzstrasse 43, 89075, Ulm, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Genze
authors.affiliation: Department of Urology, Ulm University Medical Center, Prittwitzstrasse 43, 89075, Ulm, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Winkler
authors.affiliation: Gerhard Domagk Institute of Pathology, University of Münster, Domagkstrasse 17, 48149, Münster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wardelmann
authors.affiliation: Clinic of Urology, Münster University Medical Center, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany.
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Schrader
authors.affiliation: Clinic of Urology, Münster University Medical Center, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany.
authors.forename: Julie
authors.initials: J
authors.lastname: Steinestel
mesh_terms: D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D010742:Phospholipid Ethers / Q000008:administration & dosage*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019459:Urothelium / Q000187:drug effects / Q000473:pathology
chemical_list: C406328:KCNN3 protein, human; D010742:Phospholipid Ethers; D051640:Small-Conductance Calcium-Activated Potassium Channels; C026659:edelfosine; D002118:Calcium
keywords: Edelfosine; Invasion; Metastasis; Small conductance calcium-activated potassium channel 3; Urothelial carcinoma