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

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TitleGaleterone and VNPT55 disrupts Mnk-eIF4E to inhibit prostate cancer cell migration and invasion.
Publication TypeJournal Article
Year of Publication2016
AuthorsKwegyir-Afful, AK, Bruno, RD, Purushottamachar, P, Murigi, FN, Njar, VCO
JournalFEBS J
Date Published2016 Sep 12
ISSN1742-4658
Abstract

Metastatic castration-resistant prostate cancer (mCRPC) accounts for a high percentage of prostate cancer mortality. The proprietary compound galeterone (gal) is 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 anti-proliferative 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 downregulating 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, downregulating 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. Moreover, expression of self-renewal proteins, β-Catenin, CD44 and Nanog, were 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 or treatment of all stages of prostate cancer. This article is protected by copyright. All rights reserved.

DOI10.1111/febs.13895
Alternate JournalFEBS J.
PubMed ID27618366
Grant ListR01 CA129379 / CA / NCI NIH HHS / United States
R21 CA195694 / CA / NCI NIH HHS / United States