Silibinin reverses epithelial-to-mesenchymal transition in metastatic prostate cancer cells by targeting transcription factors

Silibinin, a naturally occurring flavanone isolated from milk thistle extract, has been shown to possess strong anticancer efficacy against both androgen-dependent and androgen-independent prostate cancer, wherein it inhibits not only cell growth, but also cell invasion and metastasis. Inhibitory effects of silibinin on prostate cancer invasion, motility and migration were previously observed in the highly bone metastatic ARCaP M cell line; however, mechanisms of such efficacy are not completely elucidated. The epithelial-to-mesenchymal transition (EMT) is a crucial step in the progression of prostate cancer, reversal or inhibition of EMT by drugs thus provides a new approach to prostate cancer therapy. In the present study, we found that silibinin treatment resulted in the up-regulation of cytokeratin-18 and down-regulation of vimentin and MMP2, which was consistent with morphologic reversal of EMT phenotype leading to be epithelial. Moreover, we found that silibinin could inhibit the nuclear factor kappaB (NF-kappaB) p50 translocation via the up-regulation of I kappaB alpha protein, and possibly subsequently down-regulated the expression of two major EMT regulators, ZEB1 and SLUG transcription factors. Overall these findings demonstrate silibinin was able to reverse EMT to suppress the invasive property of metastatic prostate cancer cells at the transcriptional level.