Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway.

Abstract

The identification and development of novel nontoxic phytochemicals that target androgen and androgen receptor (AR) signaling remains a priority for prostate cancer (PCA) control. In the present study, we assessed the antiandrogenic efficacy of isosilybin B employing human PCA LNCaP (mutated AR), 22Rv1 (mutated AR) and LAPC4 (wild-type AR) cells. Isosilybin B (10-90 microM) treatment decreased the AR and prostate specific antigen (PSA) levels in LNCaP, 22Rv1 and LAPC4 cells, but not in non-neoplastic human prostate epithelial PWR-1E cells. Isosilybin B treatment also inhibited synthetic androgen R1881-induced nuclear localization of AR, PSA expression and cell growth, and caused G(1) arrest. In mechanistic studies identifying AR degradation, isosilybin B caused increased phosphorylation of Akt (Ser-473 and Thr-308) and Mdm2 (Ser-166), which was linked with AR degradation as pretreatment with PI3K inhibitor (LY294002)-restored AR level. Further, overexpression of kinase-dead Akt largely reversed isosilybin B mediated-AR degradation suggesting a critical role of Akt in AR degradation. Antibody pull-down results also indicated that isosilybin B treatment enhances the formation of complex between Akt, Mdm2 and AR, which promotes phosphorylation-dependent AR ubiquitination and its degradation by proteasome. Together, present findings identify a novel mechanism for isosilybin B-mediated anticancer effects in human PCA cells.

• Authors: G Deep, N H Oberlies, D J Kroll, R Agarwal
• Journal: Oncogene (Oncogene) Vol. 27 Issue 28 Pg. 3986-98 (Jun 26 2008) ISSN: 1476-5594 [Electronic] England
• PMID: 18332867 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Receptors, Androgen
• Silymarin
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Prostate-Specific Antigen
• Proteasome Endopeptidase Complex
• isosilybin A

Topics

• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Cytoplasm (metabolism)
• Humans
• Male
• Models, Biological
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Prostate-Specific Antigen (metabolism)
• Prostatic Neoplasms (metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-mdm2 (metabolism)
• Receptors, Androgen (metabolism)
• Silymarin (analogs & derivatives, physiology)