The retinamide VNLG-152 inhibits AR/AR-V7 and MNK-eIF4Esignaling pathways to suppress EMT and castration-resistant prostate cancer xenograft growth.

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TitleThe retinamide VNLG-152 inhibits AR/AR-V7 and MNK-eIF4Esignaling pathways to suppress EMT and castration-resistant prostate cancer xenograft growth.
Publication TypeJournal Article
Year of Publication2018
AuthorsRamamurthy, VP, Ramalingam, S, Gediya, LK, Njar, VCO
JournalFEBS J
Date Published2018 Jan 11
ISSN1742-4658
Abstract

VNLG-152, a lead novel retinamide (NR) shown to suppress growth and progression in genetically diverse PCa cells via inhibition of AR signaling and eIF4E translational machinery. Herein, we report therapeutic effects of VNLG-152 on castration resistant prostate cancer (CRPC) growth and metastatic phenotype in CRPC tumor xenograft model. Administration of VNLG-152 significantly and dose-dependently suppressed the growth of aggressive CWR22Rv1 tumors by 63.4% and 76.3% respectively (P = 0.001), vs. vehicle with no host toxicity. Strikingly, the expression of full-length/splice variant androgen receptors (f-AR/AR-V7), mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNK1/2), p-eIF4E, and their associated target proteins including PSA, Cyclin D1 and Bcl-2 were decreased in VNLG-152 treated tumors signifying inhibition of AR/AR-V7 and MNK-eIF4E signaling in VNLG-152 treated 22Rv1 tumors as observed in vitro. VNLG-152 also suppressed epithelial to mesenchymal transition (EMT) in 22Rv1 tumors as evidenced by repression of N-cadherin, β-Catenin, Claudin, Slug, Snail, Twist, and vimentin, and MMPs (MMP-2 and MMP-9) with upsurge in E-Cadherin. These results highlight the promising use of VNLG-152 in CRPC therapy and justifies its further development towards clinical trials. This article is protected by copyright. All rights reserved.

DOI10.1111/febs.14383
Alternate JournalFEBS J.
PubMed ID29323792