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Amplification of KCNMA1 : a potential therapeutic target in prostate cancer

Bloch, Michael. Amplification of KCNMA1 : a potential therapeutic target in prostate cancer. 2007, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_7887

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Abstract

Prostate cancer is the most common cancer in males and the second leading cause of cancer deaths in western countries. Although most prostate cancers initially respond well to androgen withdrawal, they become inevitably resistant to this treatment and progress to hormoneinsensitive disease after only a few months or years. The therapeutic options in these advanced tumors are very limited. The molecular mechanisms of how prostate cancers escape hormonal treatment are poorly understood. Identification of genetic alterations including amplifications could elucidate genes with oncogenic properties to be used as new therapeutic targets in this deadly disease. Here, we investigated amplification at 10q22 that prevails in 1015% of hormone-insensitive prostate cancers and in the hormone-insensitive prostate cancer cell line PC-3. A core regionMb of the amplicon was chosen for detailed analysis. The amplification profile of this region was unexpectedly flat and did not allow us to narrow down the region of interest or select a candidate gene based its location within the amplicon. A number of potentially interesting genes within the amplified region based on the established or presumed biologic functions were tested for amplification and mRNA expression status in the prostate cell lines. The calcium-activated large-conductance potassium channel (KCNMA1) was chosen for detailed analysis as it showed the most consistent association between amplification and overexpression. It was highly expressed in the prostate cancer cell line with KCNMA1 amplification (PC-3) as compared to the non-amplified cell lines LNCaP, CWR22R, and BPH-1. Other interesting candidates that are amplified at 10q22 include PLAU, VDAC2, PSAP, CAMK2G, and PPP3CB. First, we ascertained that KCNMA1 amplification prevailed also in vivo using fluorescence in situ hybridization (FISH) with a probe specific for KCNMA1. Amplification was found in 16% of 119 late-stage human prostate cancers but not in 33 benign controls, 32 precursor lesions and in 105 clinically organ-confined prostate cancers on a prostate tissue microarray.
Modulation of the BK channel activity in vitro revealed that BK channel promotes growth of
prostate cancer cell lines. In more detail, specific inhibition of BK channel in PC-3 by
iberiotoxin reduced growth of this cell line but had no significant effect on BPH-1and
LNCaP. This effect was even much more pronounced by RNA interference as shown in PC-3.
This growth inhibition by RNA interference was paralleled by changes of cell size and shape,
suggesting that BK channel may be involved in the regulation of cell volume. Interestingly,
estradiol enhanced the growth of BPH-1 and LNCaP, but did not affect the growth of PC-3.
The effect of estradiol on LNCaP and BPH-1 was prevented by iberiotoxin. This finding
suggests that estradiol mediates the effect of estradiol on the growth of prostate cells that do
not overexpress BK channel.
Taken together, our data suggest that the BK channel system is involved in the regulation of
growth of prostate cancer cell lines and putatively also in the progression of prostate cancer in
vivo. This makes KCNMA1 a potential therapeutic target in patients with prostate cancers
that harbor KCNMA1 amplification. However, further studies are needed to investigate
KCNMA1 in human prostate cancer, as we found no significant association between gene
dosage and expression in a preliminary series of fresh-frozen specimens from hormoneinsensitive
local recurrences. Similarly, the precise mechanisms by which KCNMA1
contributes to growth regulation remain to be elucidated.
Advisors:Moroni, Christoph
Committee Members:Hynes, Nancy and Bubendorf, Lukas
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Growth and Development (Moroni)
03 Faculty of Medicine > Departement Biomedizin > Former Units at DBM > Growth and Development (Moroni)
UniBasel Contributors:Moroni, Christoph and Bubendorf, Lukas
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:7887
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:73
Language:English
Identification Number:
Last Modified:22 Jan 2018 15:50
Deposited On:13 Feb 2009 16:00

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