title: KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer.
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 beta-estradiol-insensitive BK currents in PC-3 cells as compared to non-amplified control cell lines. Specific blockade of BK channels by iberiotoxin or RNA(i) 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.
authors.affiliation: Institute for Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Bloch
authors.forename: J
authors.initials: J
authors.lastname: Ousingsawat
authors.forename: R
authors.initials: R
authors.lastname: Simon
authors.forename: P
authors.initials: P
authors.lastname: Schraml
authors.forename: T C
authors.initials: TC
authors.lastname: Gasser
authors.forename: M J
authors.initials: MJ
authors.lastname: Mihatsch
authors.forename: K
authors.initials: K
authors.lastname: Kunzelmann
authors.forename: L
authors.initials: L
authors.lastname: Bubendorf
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002879:Chromosomes, Human, Pair 10; D005784:Gene Amplification / Q000502:physiology*; D006801:Humans; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits