Galeterone and VNPT55 disrupt Mnk-eIF4E to inhibit prostate cancer cell migration and invasion

FEBS J. 2016 Nov;283(21):3898-3918. doi: 10.1111/febs.13895. Epub 2016 Oct 1.

Abstract

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.

Keywords: EMT; Gal/VNPT55; Mnk1/2; eIF4E.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Androstadienes / pharmacology*
  • Animals
  • Benzimidazoles / pharmacology*
  • Cell Line
  • Cell Movement / drug effects*
  • Cell Movement / genetics
  • Eukaryotic Initiation Factor-4E / genetics
  • Eukaryotic Initiation Factor-4E / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Immunoblotting
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Mice, SCID
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Androstadienes
  • Benzimidazoles
  • Eukaryotic Initiation Factor-4E
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • VNPT55
  • MKNK1 protein, human
  • MKNK2 protein, human
  • Protein-Serine-Threonine Kinases
  • 3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene