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

Oncogene volume 25, pages 1463–1473 (2006)Cite this article

Abstract

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-κB. Diosgenin suppressed TNF-induced NF-κB activation as determined by DNA binding, activation of IκBα kinase, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, and p65 nuclear translocation through inhibition of Akt activation. NF-κB-dependent reporter gene expression was also abrogated by diosgenin. TNF-induced expression of NF-κB-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-κB-regulated gene expression and enhances apoptosis induced by cytokines and chemotherapeutic agents.

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Abbreviations

TNF:

tumor necrosis factor

RANKL:

receptor-activated nuclear factor-kappaB ligand

NF-κB:

nuclear factor-kappaB

IκB:

inhibitory subunit of NF-κB

SEAP:

secretory alkaline phosphatase

IKK:

IκBα kinase

COX-2:

cyclooxygenase-2

LOX:

lipoxygenase

MMP-9:

matrix metalloproteinase-9

FBS:

fetal bovine serum

SDS:

sodium dodecyl sulfate

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Acknowledgements

We thank Walter Pagel for a careful review of the manuscript. Dr Aggarwal is a Ransom Horne Jr Professor of Cancer Research. This work was supported in part by the Odyssey Program and the Theodore N Law Award for Scientific Achievement at The University of Texas MD Anderson Cancer Center (to SS). This work was also supported by the Clayton Foundation for Research (to BBA), a Department of Defense US Army Breast Cancer Research Program Grant (BC010610, to BBA), a PO1 Grant (CA91844) from the National Institutes of Health on lung chemoprevention (to BBA), and a P50 Head and Neck SPORE grant from the National Institutes of Health (to BBA).

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  1. Department of Experimental Therapeutics, Cytokine Research Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S Shishodia & B B Aggarwal

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Correspondence to B B Aggarwal.

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Shishodia, S., Aggarwal, B. Diosgenin inhibits osteoclastogenesis, invasion, and proliferation through the downregulation of Akt, IκB kinase activation and NF-κB-regulated gene expression. Oncogene 25, 1463–1473 (2006). https://doi.org/10.1038/sj.onc.1209194

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