Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells.
Silibinin, a naturally occurring flavonoid antioxidant found in the milk thistle, has recently been shown to have potent antiproliferative effects against various malignant cell lines, but the underlying mechanism of action remains to be elucidated. We investigated the effect of silibinin on androgen-independent prostate cancer PC-3 cells. At pharmacologically achievable silibinin concentrations (0.02-20 microM), we observed increased insulin-like growth factor-binding protein 3 (IGFBP-3) accumulation in PC-3 cell conditioned medium and a dose-dependent increase of IGFBP-3 mRNA abundance with a 9-fold increase over baseline at 20 microM silibinin. An IGFBP-3 antisense oligodeoxynucleotide that attenuated silibinin-induced IGFBP-3 gene expression and protein accumulation reduced the antiproliferative action of silibinin. We also observed that silibinin reduced insulin receptor substrate 1 tyrosine phosphorylation, indicating an inhibitory effect on the insulin-like growth factor I receptor-mediated signaling pathway. These results suggest a novel mechanism by which silibinin acts as an antiproliferative agent and justify further work to investigate potential use of this compound or its derivatives in prostate cancer treatment and prevention.
Zi
X
X
Lady Davis Research Institute of Jewish General Hospital and Department of Oncology, McGill University, Montreal, Quebec, Canada.
Zhang
J
J
Agarwal
R
R
Pollak
M
M
D000728:Androgens / Q000502:physiology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012838:Silymarin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D000728:Androgens; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D010750:Phosphoproteins; D012838:Silymarin; D007334:Insulin-Like Growth Factor I