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The retinamide VNLG ‐152 inhibits f‐AR / AR ‐V7 and MNK – eIF 4E signaling pathways to suppress EMT and castration‐resistant prostate cancer xenograft growth
Author(s) -
Ramamurthy Vidya P.,
Ramalingam Senthilmurugan,
Gediya Lalji K.,
Njar Vincent C. O.
Publication year - 2018
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14383
Subject(s) - androgen receptor , cancer research , prostate cancer , signal transduction , vimentin , cyclin d1 , chemistry , kinase , biology , cancer , microbiology and biotechnology , medicine , cell cycle , immunohistochemistry
VNLG ‐152 is a novel retinamide ( NR ) shown to suppress growth and progression of genetically diverse prostate cancer cells via inhibition of androgen receptor signaling and eukaryotic initiation factor 4E ( eIF 4E) translational machinery. Herein, we report therapeutic effects of VNLG ‐152 on castration‐resistant prostate cancer ( CRPC ) growth and metastatic phenotype in a CRPC tumor xenograft model. Administration of VNLG ‐152 significantly and dose‐dependently suppressed the growth of aggressive CWR 22Rv1 tumors by 63.4% and 76.3% at 10 and 20 mg·kg −1 bw, respectively ( P < 0.0001), vs . vehicle with no host toxicity. Strikingly, the expression of full‐length androgen receptor (f‐ AR )/androgen receptor splice variant‐7 ( AR ‐V7), mitogen‐activated protein kinase‐interacting kinases 1 and 2 ( MNK 1/2), phosphorylated eIF 4E and their associated target proteins, including prostate‐specific antigen, cyclin D1 and Bcl‐2, were strongly decreased in VNLG ‐152‐treated tumors signifying inhibition of f‐ AR / AR ‐V7 and MNK – eIF 4E signaling in VNLG ‐152‐treated CWR 22Rv1 tumors as observed in vitro . VNLG ‐152 also suppressed the epithelial to mesenchymal transition in CWR 22Rv1 tumors as evidenced by repression of N‐cadherin, β‐catenin, claudin, Slug, Snail, Twist, vimentin and matrix metalloproteinases ( MMP ‐2 and MMP ‐9) with upsurge in E‐cadherin. These results highlight the promising use of VNLG ‐152 in CRPC therapy and justify its further development towards clinical trials.