KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer.
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.
Bloch
M
M
Institute for Pathology, University Hospital Basel, Basel, Switzerland.
Ousingsawat
J
J
Simon
R
R
Schraml
P
P
Gasser
T C
TC
Mihatsch
M J
MJ
Kunzelmann
K
K
Bubendorf
L
L
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*
C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits