Regulation of Akt/FOXO3a/GSK-3beta/AR signaling network by isoflavone in prostate cancer cells.
We have previously shown that genistein could inhibit Akt activation and down-regulate AR (androgen receptor) and PSA (prostate-specific antigen) expression in prostate cancer (PCa) cells. However, pure genistein showed increased lymph node metastasis in an animal model, but such an adverse effect was not seen with isoflavone, suggesting that further mechanistic studies are needed for elucidating the role of isoflavone in PCa. It is known that FOXO3a and GSK-3beta, targets of Akt, regulate cell proliferation and apoptosis. Moreover, FOXO3a, GSK-3beta, and Src are AR regulators and regulate transactivation of AR, mediating the development and progression of PCa. Therefore, we investigated the molecular effects of isoflavone on the Akt/FOXO3a/GSK-3beta/AR signaling network in hormone-sensitive LNCaP and hormone-insensitive C4-2B PCa cells. We found that isoflavone inhibited the phosphorylation of Akt and FOXO3a, regulated the phosphorylation of Src, and increased the expression of GSK-3beta, leading to the down-regulation of AR and its target gene PSA. We also found that isoflavone inhibited AR nuclear translocation and promoted FOXO3a translocation to the nucleus. By electrophoretic mobility shift assay and chromatin immunoprecipitation assay, we found that isoflavone inhibited FOXO3a binding to the promoter of AR and increased FOXO3a binding to the p27(KIP1) promoter, resulting in the alteration of AR and p27(KIP1) expression, the inhibition of cell proliferation, and the induction of apoptosis in both androgen-sensitive and -insensitive PCa cells. These results suggest that isoflavone-induced inhibition of cell proliferation and induction of apoptosis are partly mediated through the regulation of the Akt/FOXO3a/GSK-3beta/AR signaling network. In conclusion, our data suggest that isoflavone could be useful for the prevention and/or treatment of PCa.
Li
Yiwei
Y
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201.
Wang
Zhiwei
Z
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201.
Kong
Dejuan
D
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201.
Li
Ran
R
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201.
Sarkar
Sanila H
SH
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201.
Sarkar
Fazlul H
FH
Department of Pathology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201. Electronic address: fsarkar@med.wayne.edu.
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015536:Down-Regulation / Q000187:drug effects; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007529:Isoflavones / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000517:prevention & control; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation
C410798:AR protein, human; C436291:CDKN1B protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D047908:Intracellular Signaling Peptides and Proteins; D007529:Isoflavones; D011944:Receptors, Androgen; D050760:Cyclin-Dependent Kinase Inhibitor p27; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3