Journal
PLOS ONE
Volume 12, Issue 9, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0184644
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Funding
- Seoul National University Hospital [0320140010]
- Astrazeneca Korea [0620132330]
- National Research Foundation (NRF) of Korea - Ministry of Education [2016R1D1A1A02936950]
- National Research Foundation of Korea [2016R1D1A1A02936950] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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We examined the anti-cancer effects and molecular mechanism of simvastatin in human castration-resistant prostate cancer (CRPC) cells, particularly focused on LIN28B and its target molecule, let-7 microRNA (miRNA) among the various target genes of NF-kB. A human CRPC cell line (PC3) was used in the current study. Gene expression patterns were evaluated using real time-PCR and western blot analysis. CCK-8 assay was used for assessing cell viability and proliferation, and a clonogenic assay was adopted to evaluate clonal proliferative capabilities. Induction of apoptotic cell death was analyzed via flow cytometry. Small interfering RNA (siRNA) and short-hairpin RNA (shRNA) were used for manipulating the expression of genes of interest. PC3 showed relatively higher expression levels of LIN28B and lower expression levels of let-7 miRNAs. Simvastatin treatment significantly inhibited cell viability and clonal proliferation in a dose-dependent manner. Importantly, the downregulated let-7 miRNA family was restored after simvastatin treatment. We further observed that human CRPC cells transfected with LIN28B-siRNA or shRNA also showed upregulated let-7 miRNAs. Finally, dual treatment with simvastatin and an NF-kB inhibitor (CAPE) synergistically induced apoptotic cell death, along with reduction of LIN28B expression, and restoration of let-7 miRNAs levels. Our data illustrate that simvastatin remarkably inhibits the growth of human CRPC cells by suppressing NF-kB and LIN28B and subsequently upregulating let-7 miRNAs. Moreover, concurrent treatment with simvastatin and an NF-kB inhibitor synergistically suppressed the growth of human CRPC cells, suggesting a novel therapeutic approach for human CRPC treatment.
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