Metastatic
castration-resistant
prostate cancer (mCRPC) accounts for a high percentage of
prostate cancer mortality. The proprietary compound
galeterone (gal) was designed to inhibit proliferation of
androgen/
androgen receptor (AR)-dependent
prostate cancer cell in vitro and in vivo and is currently in phase III clinical development. Additionally, clinical studies with gal revealed its superb efficacy in four different cohorts of patients with mCRPC, including those expressing splice variant AR-V7. Preclinical studies with gal show that it also exhibits strong antiproliferative activities against AR-negative
prostate cancer cells and
tumors through a mechanism involving phosphorylation of eIF2α, which forms an integral component of the eukaryotic mRNA translation complex. Thus, we hypothesized that gal and its new analog,
VNPT55, could modulate oncogenic mRNA translation and
prostate cancer cell migration and invasion. We report that gal and
VNPT55 profoundly inhibit migration and invasion of
prostate cancer cells, possibly by down-regulating
protein expression of several EMT markers (Snail, Slug,
N-cadherin,
vimentin, and
MMP-2/-9) via antagonizing the Mnk-eIF4E axis. In addition, gal/
VNPT55 inhibited both NF-κB and Twist1 transcriptional activities, down-regulating Snail and BMI-1
mRNA expression, respectively. Furthermore, profound up-regulation of
E-cadherin mRNA and
protein expression may explain the observed significant inhibition of
prostate cancer cell migration and invasion. Moreover, expression of self-renewal
proteins, β-
catenin, CD44, and Nanog, was markedly depleted. Analysis of gal/
VNPT55-treated CWR22Rv1 xenograft tissue sections also revealed that observations in vitro were recapitulated in vivo. Our results suggest that gal/
VNPT55 could become promising agents for the prevention and/or treatment of all stages of
prostate cancer.