Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, IjB kinase activation and NF-jB-regulated gene expression

Diosgenin, a steroidal saponin present in fenugreek (Trigonella foenum graecum) and other plants, has been shown to suppress inflammation, inhibit proliferation, and induce apoptosis in a variety of tumor cells, but through a mechanism that is poorly understood. In the present study, we report that diosgenin inhibits receptor-activated nuclear factor-kappaB ligand-induced osteoclastogenesis, suppresses tumor necrosis factor (TNF)-induced invasion, and blocks the proliferation of tumor cells, all activities known to be regulated by NF-jB. Diosgenin suppressed TNF-induced NF-jB activation as determined by DNA binding, activation of IjBa kinase, IjBa phosphorylation, IjBa degradation, p65 phosphorylation, and p65 nuclear translocation through inhibition of Akt activation. NF-jB-dependent reporter gene expression was also abrogated by diosgenin. TNF-induced expression of NF-jB-regulated gene products involved in cell proliferation (cyclin D1, COX-2, c-myc), antiapoptosis (IAP1, Bcl-2, Bcl-XL, Bfl-1/A1, TRAF1 and cFLIP), and invasion (MMP-9) were also downregulated by the saponin. Diosgenin also potentiated the apoptosis induced by TNF and chemotherapeutic agents. Overall, our results suggest that diosgenin suppresses proliferation, inhibits invasion, and suppresses osteoclastogenesis through inhibition of NF-jB-regulated gene expression and enhances apoptosis induced by cytokines and chemotherapeutic agents. Oncogene advance online publication, 5 December 2005; doi:10.1038/sj.onc.1209194