Fenofibrate is the most widely used lipid-lowering drug, but it seems to have anti-tumor effects in several tumor cell lines. However, there are only a few reports on its effects on human prostate cancer cells. Thus, we investigated the anti-proliferative effects of fenofibrate on human prostate cancer cells and potential mechanisms. The methods used include cell viability analysis with an MTT assay, as well as apoptosis and related signaling pathway analyses with flow cytometry and Western blotting. Fenofibrate inhibited PC-3 cell growth in dose- and time-dependent manners. The fenofibrate-induced cell death is predominantly apoptotic death that is mediated by both the caspase-3 activation and apoptosis-inducing factor (AIF) signaling pathways. Fenofibrate also increased the expression of Bad and decreased the expression of Bcl-2 and Survivin. Mechanistically, fenofibrate-induced cell death was associated with decreased p-p70S6K and the mammalian target of rapamycin (mTOR) phosphorylation levels. When further exploring the upstream mediators of mTOR/p70S6K, we found that fenofibrate increased p38 MAPK and AMPK phosphorylation but did not significantly change the phosphorylation levels of PI3K, AKT, and JNK. However, the inhibition of either p38 MAPK or AMPK with their specific inhibitor did not change the effect of fenofibrate-induced cell death. These findings suggested that fenofibrate indeed significantly inhibited the proliferation of PC-3 cells via apoptotic action, which is associated with the inactivation of the mTOR/p70S6K-dependent cell survival pathway. Although the mechanisms by which fenofibrate inactivates this pathway remains unclear, this study reveals great potential for its use for the clinical treatment of prostate cancers.
Biochemical and biophysical research communications. 2018 Jan 03 [Epub ahead of print]
Xin Lian, Junlian Gu, Baoshan Gao, Yan Li, Chendil Damodaran, Wei Wei, Yaowen Fu, Lu Cai
Department of Urology, The First Hospital of Jilin University, Changchun 130021, China; Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA., Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA., Department of Urology, The First Hospital of Jilin University, Changchun 130021, China., Department of Surgery, University of Louisville, Louisville, KY 40202, USA., Department of Urology, University of Louisville, Louisville, KY 40202, USA., Department of Urology, The First Hospital of Jilin University, Changchun 130021, China. Electronic address: ., Pediatric Research Institute, Department of Pediatrics, University of Louisville, Louisville, KY 40202, USA; Departments of Radiation Oncology, Pharmacology and Toxicology, University of Louisville, Louisville, KY 40202, USA. Electronic address: .