Ginsenoside compound K suppresses tumour growth in the 22Rv1 xenograft model and inhibits androgenic responses via the transcriptional mechanism in human prostate cancer cells.

Abstract

Androgen receptor (AR) signalling is known to be dispensable for the biology of castration-resistant prostate cancer (CRPC), whereas the AR itself and the residual androgens after castration are crucial for the growth and progression of CRPC. Therefore, there is high demand for novel therapeutic candidates targeting AR itself or aberrant AR signalling to suppress the progression to or the growth of CPRC. Here, we report that ginsenoside compound K (GCK), the primary bioactive metabolite biotransformed from protopanaxadiol (PPD) ginsenoside, acts as a novel AR signalling inhibitor by transcriptionally suppressing AR expression and tumour growth in athymic nude mice. GCK inhibited cell growth in LNCaP, PC-3 and 22Rv1 prostate cancer cell lines and suppressed the expression levels of cell cycle regulators. GCK down-regulated epithelial-mesenchymal transition markers such as vimentin and matrix metalloproteinase 9 (MMP9), whereas E-cadherin was significantly increased in GCK-stimulated LNCaP and 22Rv1 cells. Moreover, GCK treatment markedly decreased both AR and AR-V7 protein levels in LNCaP and 22Rv1 cells, possibly by decreasing AR promoter activity. Experiments with AR promoter-deleted constructs revealed that the region between -412 and -227 is critical for GCK regulation. GCK treatment in athymic nude mice implanted with 22Rv1 CRPC cell lines significantly suppressed tumour growth and AR expression levels in tumour tissues. Collectively, our results suggest that GCK, as a novel AR inhibitor, could be a potential therapeutic agent against prostate cancer and an effective chemopreventive agent to delay the progression to CRPC.