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An Orthotopic Murine Model of Human Prostate Cancer Metastasis

An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Published on: September 18, 2013

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

Andrew K Kwegyir-Afful^1,2, Robert D Bruno^1,2, Puranik Purushottamachar^1,2

¹Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, USA.

The FEBS Journal

|September 13, 2016

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.

Insights

Galeterone and VNPT55 inhibit prostate cancer cell migration and invasion by targeting mRNA translation and EMT pathways. These compounds show promise for treating all stages of prostate cancer.

Area of Science:

Oncology
Molecular Biology
Cancer Research

Background:

Metastatic castration-resistant prostate cancer (mCRPC) is a leading cause of cancer mortality.
Galeterone (gal) is a proprietary compound designed to inhibit androgen receptor (AR)-dependent prostate cancer cell proliferation.
Gal has shown efficacy in mCRPC patients, including those with AR-V7 splice variant, and antiproliferative activity in AR-negative cells via eIF2α phosphorylation.

Purpose of the Study:

To investigate the potential of galeterone (gal) and its analog VNPT55 in modulating oncogenic mRNA translation.
To assess the effects of gal and VNPT55 on prostate cancer cell migration and invasion.
To explore the underlying molecular mechanisms, including the Mnk-eIF4E axis, EMT markers, and transcriptional activities.

Main Methods:

In vitro studies on prostate cancer cell lines to evaluate migration, invasion, and protein/mRNA expression.
Analysis of epithelial-mesenchymal transition (EMT) markers (Snail, Slug, N-cadherin, vimentin, MMP-2/-9, E-cadherin).
Assessment of transcriptional activities (NF-κB, Twist1) and self-renewal proteins (β-catenin, CD44, Nanog).
In vivo studies using CWR22Rv1 xenograft models to confirm in vitro findings.

Main Results:

Galeterone and VNPT55 significantly inhibited prostate cancer cell migration and invasion.
Down-regulation of EMT markers and antagonism of the Mnk-eIF4E axis were observed.
Inhibition of NF-κB and Twist1 transcriptional activities, with subsequent down-regulation of Snail and BMI-1 mRNA.
Significant up-regulation of E-cadherin and depletion of self-renewal proteins (β-catenin, CD44, Nanog).
In vitro findings were recapitulated in vivo in xenograft models.

Conclusions:

Galeterone and VNPT55 demonstrate potent inhibition of prostate cancer cell migration and invasion.
These compounds target key pathways involved in cancer progression, including mRNA translation and EMT.
Galeterone and VNPT55 represent promising therapeutic agents for various stages of prostate cancer.

Read full analysis

Keywords:

EMT Gal/VNPT55 Mnk1/2 eIF4E

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