Premium
Galeterone and VNPT 55 disrupt Mnk‐ eIF 4E to inhibit prostate cancer cell migration and invasion
Author(s) -
KwegyirAfful Andrew K.,
Bruno Robert D.,
Purushottamachar Puranik,
Murigi Francis N.,
Njar Vincent C.O.
Publication year - 2016
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.13895
Subject(s) - prostate cancer , cancer research , tramp , biology , cancer , androgen receptor , cd44 , homeobox protein nanog , prostate , metastasis , cell , medicine , genetics , embryonic stem cell , induced pluripotent stem cell , gene , biochemistry
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 eIF 2α, which forms an integral component of the eukaryotic mRNA translation complex. Thus, we hypothesized that gal and its new analog, VNPT 55, could modulate oncogenic mRNA translation and prostate cancer cell migration and invasion. We report that gal and VNPT 55 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– eIF 4E axis. In addition, gal/ VNPT 55 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, CD 44, and Nanog, was markedly depleted. Analysis of gal/ VNPT 55‐treated CWR 22Rv1 xenograft tissue sections also revealed that observations in vitro were recapitulated in vivo . Our results suggest that gal/ VNPT 55 could become promising agents for the prevention and/or treatment of all stages of prostate cancer.