PURPOSE: In castrate resistant prostate cancer cells we investigated the cytotoxic effect of simvastatin and the mechanism involved.
MATERIALS AND METHODS: After treating PC3 and DU-145 cells with simvastatin, cell viability and apoptosis were determined using tetrazolium salt based colorimetric assay and annexin-V-fluorescein isothiocyanate/propidium iodide double staining assay, respectively. To determine whether simvastatin affects the nuclear factor-κB pathway, we assessed IκBα and phosphorylated IκBα expression, and p65 and phosphorylated p65 subcellular localization by Western blot analysis. Also, changes in nuclear factor-κB transcriptional activity were assessed using a luciferase reporter assay.
RESULTS: After treating PC3 and DU-145 cells with 0, 20 or 40 μM simvastatin for 24, 48 or 72 hours, the proportion of viable cells decreased and the proportion of apoptotic cells increased in a dose and time dependent manner. Western blot analysis showed that simvastatin inhibited IκBα phosphorylation and degradation. It also demonstrated that simvastatin increased p65 protein levels in cytoplasmic fractions and decreased phosphorylated p65 protein levels in nuclear fractions but did not change p65 protein levels in cytoplasm. Luciferase reporter assay showed that simvastatin dose dependently reduced nuclear factor-κB activity. Reverse transcriptase-polymerase chain reaction and Western blot revealed that simvastatin inhibited nuclear factor-κB regulated cIAP-1 and 2, cFLIP-S and XIAP expression in dose and time dependent fashion.
CONCLUSIONS: Simvastatin inhibited castrate resistant prostate cancer cell growth by inducing apoptosis. These effects were probably mediated by the inhibition of IκBα phosphorylation and nuclear translocation of p50/p65 dimer in the nuclear factor-κB pathway.
Written by:
Park YH, Seo SY, Lee E, Ku JH, Kim HH, Kwak C. Are you the author?
Seoul National University Hospital, Seoul, Korea.
Reference: J Urol. 2012 Oct 22. pii: S0022-5347(12)05258-5.
doi: 10.1016/j.juro.2012.10.030
PubMed Abstract
PMID: 23085058
UroToday.com Investigative Urology Section
