PubMed:18332867
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/18332867","sourcedb":"PubMed","sourceid":"18332867","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/18332867","text":"Isosilybin B causes androgen receptor degradation in human prostate carcinoma cells via PI3K-Akt-Mdm2-mediated pathway.\nThe 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.","tracks":[{"project":"CoMAGC","denotations":[{"id":"T1","span":{"begin":521,"end":523},"obj":"Gene"},{"id":"E1","span":{"begin":560,"end":566},"obj":"Gene_expression"},{"id":"E2","span":{"begin":507,"end":516},"obj":"Negative_regulation"},{"id":"T2","span":{"begin":652,"end":658},"obj":"prostate cancer"},{"id":"T3","span":{"begin":570,"end":575},"obj":"prostate cancer"},{"id":"T4","span":{"begin":587,"end":592},"obj":"prostate cancer"},{"id":"T5","span":{"begin":577,"end":582},"obj":"prostate cancer"}],"relations":[{"id":"R3","pred":"IGE-","subj":"T1","obj":"T2"},{"id":"R1","pred":"themeOf","subj":"T1","obj":"E1"},{"id":"R2","pred":"themeOf","subj":"E1","obj":"E2"},{"id":"R3","pred":"CGE-decreased","subj":"T1","obj":"T2"},{"id":"R4","pred":"CCS-unidentifiable","subj":"T1","obj":"T2"},{"id":"R5","pred":"PT-","subj":"T1","obj":"T2"}],"attributes":[{"subj":"T1","pred":"source","obj":"CoMAGC"},{"subj":"E1","pred":"source","obj":"CoMAGC"},{"subj":"E2","pred":"source","obj":"CoMAGC"},{"subj":"T2","pred":"source","obj":"CoMAGC"},{"subj":"T3","pred":"source","obj":"CoMAGC"},{"subj":"T4","pred":"source","obj":"CoMAGC"},{"subj":"T5","pred":"source","obj":"CoMAGC"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"CoMAGC","color":"#d0ec93","default":true}]}]}}