The chemopreventive retinoid 4HPR impairs prostate cancer cell migration and invasion by interfering with FAK/AKT/GSK3β pathway and β-catenin stability

Molecular Cancer

Research

Roberta Venè¹  Roberto Benelli²  Nicoletta Ferrari²  Stefano Monteghirfo²  Francesca Tosetti² 

[1] Biologia Cellulare, Istituto Nazionale per la Ricerca sul Cancro, Largo R.Benzi 10, 16132, Genova, Italy;Oncologia Molecolare e Angiogenesi, Istituto Nazionale per la Ricerca sul Cancro, Largo R.Benzi 10, 16132, Genova, Italy;

关键词: Prostate Cancer;    Prostate Cancer Cell;    Focal Adhesion Kinase;    DU145 Cell;    4HPR;   

DOI  :  10.1186/1476-4598-9-142

 received in 2009-12-21, accepted in 2010-06-10,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundProstate 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.ResultsWe found that 4HPR impairs DU145 and PC3 prostate cancer cells migration and invasion by down-regulating FAK and AKT activation and by enhancing β-catenin degradation, 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 β-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 β-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, β-catenin stability and cyclin D1 expression.ConclusionThese data point to 4HPR as a negative regulator of AKT phosphorylation, effectively targeting the β-catenin pathway and inducing a relatively benign phenotype in prostate cancer cells, limiting neoangiogenesis and cell invasion.

【 授权许可】

Unknown   
© Benelli et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.