Role of E-cadherin in antimigratory and antiinvasive efficacy of silibinin in prostate cancer cells

• Published in: Cancer prevention research (Philadelphia, Pa.) Pa.), 2011-08, Vol.4 (8), p.1222-1232
• Main Authors: Deep, Gagan, Gangar, Subhash Chander, Agarwal, Chapla, Agarwal, Rajesh
• Format: Article
• Language: English
• Subjects: Antioxidants - pharmacology; Cadherins - physiology; Cell Line, Tumor; Cell Movement; Cell Survival; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Male; Microscopy, Confocal - methods; Neoplasm Invasiveness; Prostatic Neoplasms - drug therapy; Silymarin - pharmacology; src-Family Kinases - metabolism; Wound Healing
• ISSN: 1940-6207; 1940-6215
• DOI: 10.1158/1940-6207.CAPR-10-0370

The epithelial-to-mesenchymal transition (EMT) in prostate cancer (PCA) cells is considered prerequisite for acquiring migratory/invasive phenotype, and subsequent metastasis. We hypothesized that promoting the E-cadherin expression in PCA cells by using nontoxic phytochemicals, like silibinin, would prevent EMT and consequently invasiveness. Our results showed that silibinin treatment (5-90 μmol/L) significantly inhibits migratory and invasive potential of advance human PCA PC3, PC3MM2, and C4-2B cells in in vitro assays. Importantly, the antimigratory/antiinvasive efficacy of silibinin was not due to its cytotoxicity toward PCA cells. Molecular analyses showed that silibinin increases E-cadherin level that was localized mainly at cellular membrane as evidenced by subcellular fractional and confocal analyses in PC3 cells, which might be responsible for morphologically observed shift toward epithelial character. Silibinin also decreased the levels of Slug, Snail, phospho-Akt(ser(473)), nuclear β-catenin, phospho-Src(tyr(419)) and Hakai; together they play an important role in regulating E-cadherin expression/function and EMT. Similar silibinin effects on E-cadherin, β-catenin, phospho-Src(tyr(419)), and Hakai levels were also observed in PC3MM2 and C4-2B PCA cells. Selective Src inhibition by dasatinib also showed increased E-cadherin expression in PC3 cells suggesting a possible involvement of Src inhibition in silibinin-caused increase in E-cadherin level. Additional studies in PC3 cells with stable knock-down of E-cadherin expression revealed that antimigratory/antiinvasive efficacy of silibinin is in-part dependent on E-cadherin expression. Together, our results showing antimigratory/antiinvasive effects of silibinin and associated mechanisms suggest that silibinin should be tested further in clinically relevant animal models toward exploiting its potential benefits against metastatic PCA.