BACKGROUND:
Prostate cancer shows an extremely slow progression, appearing in its metastatic, hormone refractory phenotype mostly in elderly men. The chemopreventive targeting of this tumor could accordingly delay its malignancy over life expectancy. The cancer chemopreventive retinoid N-(4 hydroxyphenyl)retinamide (4HPR) has already been shown to restrain prostate cancer growth in vitro and in vivo, though its mechanisms of action are only partially explained.
RESULTS:
We found that 4HPR impairs DU145 and PC3 prostate cancer cells migration and invasion by down-regulating FAK and AKT activation and by enhancing beta-catenin degradation, 12could acc causing the downregulation of target genes like cyclin D1, survivin and VEGF. This non-migratory
phenotype was similarly produced in both cell lines by stable silencing of beta-catenin. 4HPR was able to decrease AKT phosphorylation also when powerfully upregulated by IGF-1 and, consequently, to impair IGF-1-stimulated cell motility. Conversely, the expression of constitutively active AKT (myr-AKT) overcame the effects of 4HPR and beta-catenin-silencing on cell migration. In addition, we found that BMP-2, a 4HPR target with antiangiogenic activity, decreased prostate cancer cell proliferation, migration and invasion by down-regulating the pathway described
involving AKT phosphorylation, beta-catenin stability and cyclin D1 expression.
CONCLUSION:
These data point to 4HPR as a negative regulator of AKT phosphorylation, effectively targeting the beta-catenin pathway and inducing a relatively benign phenotype in prostate cancer cells, limiting neoangiogenesis and cell invasion.
The chemopreventive retinoid 4HPR impairs prostate cancer cell migration and invasion by interfering with FAK/AKT/GSK3beta pathway and beta-catenin stability
Riferimento:
Mol Cancer. 2010 Jun 10;9:142.
Autori:
Benelli R, Monteghirfo S, Venè R, Tosetti F, Ferrari N.
Fonte:
Mol Cancer. 2010 Jun 10;9:142.
Anno:
2010
Azione:
Il retinoide N-(4 idrossifenil) retinamide (4HPR) ha dimostrato di frenare la crescita del cancro della prostata in vitro e in vivo, limitando la neoangiogenesi e l'invasione cellulare.
Target:
4HPR/cancro della prostata.
Sostanze: