Title:Platycodin D Induces Tumor Growth Arrest by Activating FOXO3a Expression in Prostate Cancer in vitro and in vivo
VOLUME: 14 ISSUE: 9
Author(s):Rui Zhou, Zongliang Lu, Kai Liu, Jing Guo, Jie Liu, Yong Zhou, Jian Yang, Mantian Mi and Hongxia Xu
Affiliation:Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China.
Keywords:Cell cycle, FOXO3a, MDM2, Platycodin D, prostate cancer.
Abstract:Platycodin D (PD), a major saponin derived from Platycodin grandiflorum, exerted
cytotoxicity against prostate cancer cell lines (PC3, DU145 and LNCaP cells) with IC50 values in the
range of 11.17 to 26.13μmol/L, whereas RWPE-1cells (a non-malignant human prostate epithelial cell
line) were not significantly affected. A further study in these cell lines showed that PD could potently
affect cell proliferation (indicated by the bromodeoxyuridine assay), induce cell apoptosis (determined by
Annexin V-FITC flow cytometry) and cause cell cycle arrest (indicated by PI staining). After being treated with PD for 48
hours, DU145 and LNCaP cells were arrested in the G0 /G1 phase, and PC3 cells were arrested in the G2/M phase. A
Western blotting analysis indicated that PD increased the expression of the FOXO3a transcription factor, decreased the
expression of p-FOXO3a and MDM2 and increased the expression of FOXO-responsive genes, p21 and p27. MDM2
silencing (transiently by siRNA-MDM2) increased the PD-induced FOXO3a protein expression, while MDM2
overexpression (in cells transiently transfected with a pcDNA3-MDM2 plasmid) decreased the PD-induced expression of
the FOXO3a protein. Moreover, PD dose-dependently inhibited the growth of PC3 xenograft tumors in BALB/c nude
mice. A Western blotting analysis of the excised xenograft tumors indicated that similar changes in protein expression
also occurred in vivo. These results suggest that PD exhibits significant activity against prostate cancer in vitro and in
vivo. The FOXO3a transcription factor appears to be involved in the activity of PD. Together, all of these findings provide
a basis for the future development of this agent for human prostate cancer therapy.
