Carcinogenesis Advance Access originally published online on March 6, 2007
Carcinogenesis 2007 28(7):1463-1470; doi:10.1093/carcin/bgm042
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Silibinin inhibits constitutive activation of Stat3, and causes caspase activation and apoptotic death of human prostate carcinoma DU145 cells
1 Department of Pharmaceutical Sciences, School of Pharmacy
2 University of Colorado Cancer Center, University of Colorado Health Sciences Center, 4200 East 9th Avenue, PO Box C238, Denver, CO 80262, USA
* To whom correspondence should be addressed. Tel: +303 315 1381, Fax: +303 315 6281; Email: rajesh.agarwal{at}uchsc.edu
Transcription factor signal transducer and activator of transcription (Stat)-3 is activated constitutively in prostate cancer (PCA) suggesting that its disruption could be an effective approach to control this malignancy. Here we assessed whether silibinin, a flavanone from Silybum marianum with proven anticancer efficacy in various cancer models, inhibits Stat3 activation in DU145 cells, and if it does, what is the biological fate of the cells? At 50 µM or higher concentrations for 24 or 48 h, silibinin concentration dependently reduced constitutive Stat3 phosphorylation at Tyr705 and Ser727 residues under both serum and serum-starved conditions. Constitutively active Stat3–DNA binding was also inhibited concentration dependently by silibinin; however, apoptotic death together with caspase and poly(ADP-ribose) polymerase (PARP) cleavage was observed by silibinin only under serum-starved conditions suggesting that additional survival pathways are active under serum conditions. In other studies, cells were treated with various specific pharmacological inhibitors where phosphorylation of Stat3 was not reduced by epidermal growth factor receptor and Mitogen activated protein/extracellular signal regulate kinase kinase (MEK1/2) inhibitors, suggesting lack of significant roles of these in Stat3 activation in DU145 cells. Janus kinase (JAK)-1 and JAK2 inhibitors strongly reduced Stat3 phosphorylation but did not result in apoptotic cell death. Interestingly, JAK1 inhibitor only in combination with silibinin resulted in a complete reduction in Stat3 phosphorylation at Tyr705, activated caspase-9 and caspase-3, and caused strong PARP cleavage and apoptotic death of DU145 cells. Given a critical role of Stat3 activation in PCA, our results showed that silibinin inhibits constitutively active Stat3 and induces apoptosis in DU145 cells, and thus might have potential significance in therapeutic intervention of this deadly malignancy.
Abbreviations: EGFR, epidermal growth factor receptor; ELISA, enzyme-linked immunosorbent assay; EMSA, electrophoretic mobility shift assay; JAK, Janus kinase; PARP, poly(ADP-ribose) polymerase; PCA, prostate cancer; Stat, signal transducer and activator of transcription
Received January 5, 2007; revised February 13, 2007; accepted February 16, 2007.
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