Salinomycin inhibits prostate cancer growth and migration via induction of oxidative stress.
BACKGROUND
We have shown that a sodium ionophore monensin inhibits prostate cancer cell growth. A structurally related compound to monensin, salinomycin, was recently identified as a putative cancer stem cell inhibitor.


METHODS
The growth inhibitory potential of salinomycin was studied in a panel of prostate cells. To get insights into the mechanism of action, a variety of assays such as gene expression and steroid profiling were performed in salinomycin-exposed prostate cancer cells.


RESULTS
Salinomycin inhibited the growth of prostate cancer cells, but did not affect non-malignant prostate epithelial cells. Salinomycin impacted on prostate cancer stem cell functions as evidenced by reduced aldehyde dehydrogenase activity and the fraction of CD44(+) cells. Moreover, salinomycin reduced the expression of MYC, AR and ERG, induced oxidative stress as well as inhibited nuclear factor-κB activity and cell migration. Furthermore, profiling steroid metabolites revealed increased levels of oxidative stress-inducing steroids 7-ketocholesterol and aldosterone and decreased levels of antioxidative steroids progesterone and pregnenolone in salinomycin-exposed prostate cancer cells.


CONCLUSIONS
Our results indicate that salinomycin inhibits prostate cancer cell growth and migration by reducing the expression of key prostate cancer oncogenes, inducing oxidative stress, decreasing the antioxidative capacity and cancer stem cell fraction.
Medical Biotechnology, VTT Technical Research Centre of Finland, University of Turku, PL 106, FI-20521 Turku, Finland.
K
K
Ketola
M
M
Hilvo
T
T
Hyötyläinen
A
A
Vuoristo
A-L
AL
Ruskeepää
M
M
Orešič
O
O
Kallioniemi
K
K
Iljin
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009534:Niclosamide / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011714:Pyrans / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D016593:Terfenadine / Q000494:pharmacology; D000095662:Polyether Polyketides
D000444:Aldehyde Dehydrogenase; D016328:NF-kappa B; D009534:Niclosamide; D011714:Pyrans; D017382:Reactive Oxygen Species; D011944:Receptors, Androgen; D016593:Terfenadine; C010327:salinomycin; D000095662:Polyether Polyketides