Abstract
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-κB. 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-κB 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-κB and LIN28B and subsequently upregulating let-7 miRNAs. Moreover, concurrent treatment with simvastatin and an NF-κB inhibitor synergistically suppressed the growth of human CRPC cells, suggesting a novel therapeutic approach for human CRPC treatment.
Highlights
The incidence of prostate cancer (PCa) has increased rapidly over the decades and has become a crucial health issue world-wide [1]
We found that PC3, a well-known human castration-resistant prostate cancer (CRPC) cell line, showed relatively higher mRNA and protein expression of LIN28B compared to those in normal prostate cells (RWPE-1), respectively (Fig 1A-a and 1A-b)
We confirmed that human CRPC cells had significantly lower expression levels of all let-7 miRNA family members compared to those in RWPE-1 cells using quantitative reverse transcriptase-polymerase chain reaction (qPCR) analysis (Fig 1B)
Summary
The incidence of prostate cancer (PCa) has increased rapidly over the decades and has become a crucial health issue world-wide [1]. If patients with PCa progress to castration-resistant prostate cancer (CRPC), they mostly die within 24 months after the diagnosis of CRPC [3]. Systemic chemotherapy and/or androgen receptor (AR)-targeted agents are regarded as treatments of choice for CRPC, treatment is hindered by adverse effects and drug-resistance [4]. In this context, development of alternate agents with good efficacy and minimal adverse effects is urgently needed for treating patients with CRPC. In addition to the accumulating evidence for the anti-cancer efficacy of statins, we have found that human CRPC cells (PC3 and DU145) show high expression of NF-κB and that simvastatin treatment induces apoptotic cell death by downregulation of activated NF-κB signaling [7]. The detailed molecular mechanisms underlying the anti-cancer effects of simvastatin remain unclear
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