Plumbagin inhibits prostate carcinogenesis in intact and castrated PTEN knockout mice via targeting PKCε Stat3 and epithelial to mesenchymal transition markers

摘要

Prostate cancer (PCa) continues to remain the most common cancer and the second leading cause of cancer-related deaths in American males. The Pten deletions and/or mutations are frequently observed in both primary prostate cancers and metastatic prostate tissue samples. Pten deletion in prostate epithelium in mice results in prostatic intraepithelial neoplasia (PIN), followed by progression to invasive adenocarcinoma. The Pten conditional knockout mice (Ptenloxp/loxp:PB-Cre4) ((Pten-KO) ) provide a unique preclinical model to evaluate agents for efficacy for both the prevention and treatment of prostate cancer (PCa). We present here for the first time that dietary plumbagin (PL), a medicinal plant-derived naphthoquinone (200 or 500 ppm) inhibits tumor development in intact as well as castrated Pten-KO mice. PL has shown no signs of toxicity at either of these doses. PL treatment resulted in a decrease expression of PKCε, AKT, Stat3 and COX2 compared to the control mice. PL treatment also inhibited the expression of vimentin and slug, the markers of epithelial to mesenchymal transition (EMT) in prostate tumors. In summary, the results indicate that dietary PL inhibits growth of both primary and castration resistant prostate cancer (CRPC) in Pten-KO mice, possibly via inhibition of PKCε, Stat3, AKT, and EMT markers (vimentin and slug), which are linked to the induction and progression of PCa.