期刊
ONCOTARGET
卷 5, 期 9, 页码 2462-2474出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1790
关键词
Y-box potein-1; Fisetin; EMT; Prostate cancer; invasion; migration
资金
- US PHS [RO1 CA160867]
- Regione Autonoma della Sardegna within the frame of Legge regionale no 7/2007 [CRP-25920]
Epithelial-to-mesenchymal transition (EMT) plays an important role in prostate cancer (PCa) metastasis. The transcription/translation regulatory Y-box binding protein-1 (YB-1) is known to be associated with cancer metastasis. We observed that YB-1 expression increased with tumor grade and showed an inverse relationship with E-cadherin in a human PCa tissue array. Forced YB-1 expression induced a mesenchymal morphology that was associated with down regulation of epithelial markers. Silencing of YB-1 reversed mesenchymal features and decreased cell proliferation, migration and invasion in PCa cells. YB-1 is activated directly via Akt mediated phosphorylation at Ser(102) within the cold shock domain (CSD). We next identified fisetin as an inhibitor of YB-1 activation. Computational docking and molecular dynamics suggested that fisetin binds on the residues from beta 1- beta 4 strands of CSD, hindering Akt's interaction with YB-1. Calculated free binding energy ranged from -11.9845 to -9.6273 kcal/mol. Plasmon Surface Resonance studies showed that fisetin binds to YB-1 with an affinity of approximately 35 mu M, with both slow association and dissociation. Fisetin also inhibited EGF induced YB-1 phosphorylation and markers of EMT both in vitro and in vivo. Collectively our data suggest that YB-1 induces EMT in PCa and identify fisetin as an inhibitor of its activation.
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