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MOLECULAR MECHANISMS FOR SILIBININ CHEMOPREVENTIVE EFFICACY AGAINST PROSTATE CANCER
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- SILIBININ EFFECTS ON CELL SIGNALING IN PROSTATE CANCER CELLS
- SILIBININ INHIBITS PROLIFERATION OF PROSTATE CANCER CELLS
- SILIBININ INDUCES APOPTOSIS IN PROSTATE CANCER CELLS
- SILIBININ INHIBITS INVASION AND METASTASIS OF PROSTATE CANCER CELLS
MOLECULAR MECHANISMS FOR SILIBININ CHEMOPREVENTIVE EFFICACY AGAINST PROSTATE CANCERSilibinin has been shown to potently inhibit prostate cancer through targeting multiple cell signaling pathways, decreasing proliferation, inducing apoptosis, and inhibiting invasion, metastasis, and angiogenesis. The specific molecular targets of silibinin that induce broad-spectrum efficacy against prostate cancer are summarized in Fig. 2. SILIBININ EFFECTS ON CELL SIGNALING IN PROSTATE CANCER CELLSSilibinin has been shown to disrupt several signaling pathways known to be important in the development and progression of prostate cancer. Treatment of prostate cancer cells with silibinin abrogated constitutive activation of STAT-3 in DU145 cells (99), disrupted EGFR signaling in LNCaP and DU145 cells (100,101), targeted IGFR signaling in PC3 cells (102), the Wnt/β-catenin pathway in PC3 and DU145 cells (103), and AR signaling in LNCaP cells both directly by reducing nuclear localization of the receptor (104) and indirectly through downregulation of a co-activator, prostate epithelium-derived Ets transcription factor (105,106). Disruption of EGF signaling by silibinin in prostate cancer cells was associated with a decrease in secreted transforming growth factor-α and modulation of MAPK activity of both ERK1/2 and JNK1/2 (101). Disruption of the Wnt/β-catenin pathway involved modulation of a co-receptor, the low-density lipoprotein receptor-related protein-6 (LRP6) (103). Silibinin inhibited the promoter activity, mRNA, basal expression, as well as phosphorylation of LRP6 (103). Silibinin also dose-dependently induced mRNA for insulin-like growth factor-binding protein-3 (IGFBP-3) which translated into higher concentrations of IGFBP-3 in PC3 conditioned medium (102). In accordance with this finding, silibinin feeding of mice was found to upregulate both circulating plasma and tumor levels of IGFBP-3 and a decreased loss of differentiation in their tumors (36,107,108). Finally, silibinin was found in several studies to broadly alter NF-κB signaling (109,110). It inhibited the constitutive activation of NF-κB found in prostate carcinoma DU145 cells, decreasing IKKα kinase activity, the resultant ratio of phospho-IκBα to IκBα, and ultimately, the translocation of p50 and p65 NF-κB subunits to the nucleus (109). SILIBININ INHIBITS PROLIFERATION OF PROSTATE CANCER CELLSMultiple studies have shown that silibinin inhibits prostate cancer cell proliferation (111–114). In addition, mice fed with silibinin exhibited decreased tumor growth both in xenograft as well as transgenic models of prostate cancer (107,108,115–117). These phenomena were in part due to potent cell cycle arrest induced by silibinin in prostate cancer cells (111). Silibinin mediated G1 arrest in prostate cancer cells by modulating a plethora of elements in the cyclins–CDKs–CDKIs pathway: decreasing protein levels of cyclin D1, cyclin D3, cyclin E, CDK4, CDK6, and CDK2, and kinase activity of CDK2 and CDK4, increasing CDKIs Kip1/p27 and Cip1/p21, and sequestering cyclin D1 and CDK2 in the cytoplasm (108,111,113,118,119). In addition, silibinin induced a marked increase in Rb levels, principally in the hypophosphorylated retinoblastoma Rb/p107 and Rb2/p130, as well as a marked decrease in levels of the transcription factors, E2F3, E2F4, and E2F5 which altogether serves to inhibit cell cycle progression (113,118). Furthermore, silibinin mediated G2-M arrest by modulating the Chk2–Cdc25C–Cdc2/cyclin B1 pathway and decreasing levels of cyclin A, cyclin B1, both total and phosphorylated Cdc2, Cdc25B, and Cdc25C phosphatases, and inhibiting Cdc2 kinase activity (111,120,121). The inhibition of Cdc25C phosphatases combined with increased checkpoint kinase-2 phosphorylation resulted in the translocation of nuclear Cdc25C to the cytoplasm as a result of increased phosphorylation (111). This was accompanied by an increased binding with 14–3-3β (111). In addition, silibinin has been reported to inhibit both telomerase as well as DNA topoisomerase IIα activity in LNCaP and DU145 cells, respectively (105,122). Interestingly, both mitoxantrone and doxorubicin were found to synergize with silibinin in inhibiting prostate cancer cell proliferation (121,123), and cisplatin and carboplatin were found to synergize with silibinin in inducing G2-M arrest corresponding to potent downregulation of Cdc2, cyclin B1, and Cdc25c (124). Together, these findings suggest the potential for combinatorial treatments to arrest prostate cancer progression. SILIBININ INDUCES APOPTOSIS IN PROSTATE CANCER CELLSStudies have shown that silibinin also initiates apoptosis in prostate cancer cells under certain treatment conditions (99,107,108,124,125). The mechanism appeared to be a consequence of decreased Bcl-2 and survivin levels, caspase activation (caspases 3, 9, and 7), subsequent cytochrome c release from mitochondria, and ultimately apoptosis (99,107,108,124). Interestingly, mitoxantrone, doxorubicin, cisplatin, and carboplatin were each found to synergize with silibinin in inducing apoptosis in prostate cancer cells (121,123,124). SILIBININ INHIBITS INVASION AND METASTASIS OF PROSTATE CANCER CELLSMultiple studies have revealed that silibinin initiates a shift of treated advanced prostate cancer cells back into an epithelial phenotype and inhibits metastasis (110,116,117,126). It was reported that in PC3, PC3MM2, and C4-2B cells, silibinin upregulated E-cadherin on their cell surface, significantly inhibiting their migratory and invasive potential (126). This phenomenon appeared to be a result of downregulation of epithelial to mesenchymal transition (EMT) regulatory molecules Slug, Snail, phospho-Akt (ser473), nuclear β-catenin, phospho-Src (tyr419), and Hakai (126). This silibinin-induced increase in E-cadherin was also found in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model in which silibinin decreased levels of MMPs, Snail, fibronectin, and vimentin translating into a reduction in cancer metastasis (116,117). Other studies found ARCaPM cells treated with silibinin exhibited decreased expression of major EMT regulators, the transcription factors ZEB1 and Slug, corresponding with decreased expression of EMT markers, vimentin and MMP-2, together translating into dose- and time-dependent reduction of invasion, motility, and migration (110,127). Along with MMP-2, silibinin has been found to inhibit MMP-9 expression in human prostate carcinoma cell lines (116,117). жүктеу/скачать 2.54 Mb. Достарыңызбен бөлісу:
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