Silibinin suppresses growth of human colorectal carcinoma SW480 cells in culture and xenograft through down-regulation of beta-catenin-dependent signaling.
Mutations in APC/beta-catenin resulting in an aberrant activation of Wnt/beta-catenin pathway are common in colorectal cancer (CRC), suggesting that targeting the beta-catenin pathway with chemopreventive/anticancer agents could be a potential translational approach to control CRC. Using human CRC cell lines harboring mutant (SW480) versus wildtype (HCT116) APC gene and alteration in beta-catenin pathway, herein we performed both in vitro and in vivo studies to examine for the first time whether silibinin targets beta-catenin pathway in its efficacy against CRC. Silibinin treatment inhibited cell growth, induced cell death, and decreased nuclear and cytoplasmic levels of beta-catenin in SW480 but not in HCT116 cells, suggesting its selective effect on the beta-catenin pathway and associated biologic responses. Other studies, therefore, were performed only in SW480 cells where silibinin significantly decreased beta-catenin-dependent T-cell factor-4 (TCF-4) transcriptional activity and protein expression of beta-catenin target genes such as c-Myc and cyclin D1. Silibinin also decreased cyclin-dependent kinase 8 (CDK8), a CRC oncoprotein that positively regulates beta-catenin activity, and cyclin C expression. In a SW480 tumor xenograft study, 100- and 200-mg/kg doses of silibinin feeding for 6 weeks inhibited tumor growth by 26% to 46% (P < .001). Analyses of xenografts showed that similar to cell culture findings, silibinin decreases proliferation and expression of beta-catenin, cyclin D1, c-Myc, and CDK8 but induces apoptosis in vivo. Together, these findings suggest that silibinin inhibits the growth of SW480 tumors carrying the mutant APC gene by down-regulating CDK8 and beta-catenin signaling and, therefore, could be an effective agent against CRC.
Kaur
Manjinder
M
Department of Pharmaceutical Sciences, School of Pharmacy, Aurora, CO, USA.
Velmurugan
Balaiya
B
Tyagi
Alpna
A
Agarwal
Chapla
C
Singh
Rana P
RP
Agarwal
Rajesh
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D056850:Cyclin-Dependent Kinase 8 / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D015398:Signal Transduction / Q000187:drug effects*; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D051153:Wnt Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D000975:Antioxidants; D012838:Silymarin; D051153:Wnt Proteins; D051176:beta Catenin; D000077385:Silybin; D056850:Cyclin-Dependent Kinase 8
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