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

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 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 and invasion. 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.

The retinamide VNLG‐152 inhibits f‐AR/AR‐V7 and MNK–eIF4E signaling pathways to suppress EMT and castration‐resistant prostate cancer xenograft growth

“…Enhanced activation of eIF4E is another common feature in advanced prostate cancer . In the nucleus, eIF4E associates with a subset of mRNAs containing ‘ 4E‐sensitivity elements ’ in their 3′‐untranslated regions and promotes their export through nuclear pores.…”

Targeting of protein translation as a new treatment paradigm for prostate cancer

“…Pre-clinical studies in prostate cancer cells have shown that eIF4E phosphorylation initiated by MNK activation can lead to epithelial mesenchymal transition (EMT) and thus affect migration and invasion of these cells. EMT markers implicated in extracellular matrix degradation and remodeling such as MMP-2/3/9, in addition to Snail and N-cadherin, have been shown to be tightly regulated by the MNK-eIF4E axis [33]. Several other genes implicated in malignant prostatic disease, such as c-FLIP, cyclin D1, VEGF, c-Myc, HIF1α and ornithine decarboxylase, are also regulated by eIF4E [34,35].…”

“…Other studies have implicated eIF4E phosphorylation in the expression of stem cell factors such as Oct-4, Nanog, CD44 and β-catenin in several cancers, including prostate cancer. A recent study by Kwegyir-Afful et al [33] showed that silencing of MNK1resulted in a marked downregulation of eIF4E phosphorylation with resultant dramatic depletion of BMI-1, Nanog and β-catenin. Regulation of BMI-1 by the MNK-eIF4E axis is especially significant in prostate cancer as BMI-1 has been reported to be upregulated and implicated in docetaxel resistance [38].…”

“…MNK degraders comprise of novel retinamides, galeterone (gal), and gal analogs (e.g., VNPT55) which have shown promise in inhibiting eIF4E activation and tumor growth in prostate, breast and pancreatic cancers [33,64–67]. MNK inhibitors, including CGP052088, CGP57380, cercosporamide, and 5-(2-(phenyloamino)pyrymidin-4-yl)thiazole-2(3H)-one derivatives, have also been well studied [58].…”

“…C-4 heteroaryl 13-cis-retinamides were also found to induce MNK1/2 degradation via the ubiquitin–proteasome pathway, with resultant depletion of peIF4E in human breast/prostate cancer cells in vitro and MDA-MB-231 breast cancer/CWR22Rv1 prostate cancer xenografts in vivo [66]. By antagonizing the MNK-eIF4E axis, galeterone (gal) and its analog VNPT55 were found to profoundly inhibit migration and invasion in human prostate cancer cells and CWR22Rv1 tumor xenografts, possibly through modulation of several EMT- associated proteins such as snail, slug, N-cadherin, vimentin, and MMP-2/9 [33]. Gal and its analogs (VNPT55, VNPP414 and VNPP433-3β) have also been recently found to downregulate MNK1/2 and peIF4E with associated induction of G1 cell cycle arrest, caspase 3-mediated cell-death, and inhibition of cell migration/invasion in gemcitabine-sensitive and –resistant pancreatic ductal adenocarcinoma (PDAC) cells.…”