Butein, a tetrahydroxychalcone, suppresses cancer-induced osteoclastogenesis through inhibition of receptor activator of nuclear factor-kappaB ligand signaling.

Abstract

Osteoclastogenesis is associated with aging and various age-related inflammatory chronic diseases, including cancer. Receptor activator of nuclear factor-kappaB (NF-κB) ligand (RANKL), a member of the tumor necrosis factor superfamily, has been implicated as a major mediator of bone resorption, suggesting that agents that can suppress RANKL signaling might inhibit osteoclastogenesis, a process closely linked to bone resorption. We therefore investigated whether butein, a tetrahydroxychalcone, could inhibit RANKL signaling and suppress osteoclastogenesis induced by RANKL or tumor cells. We found that human multiple myeloma cells (MM.1S and U266), breast tumor cells (MDA-MB-231) and prostate tumor cells (PC-3) induced differentiation of macrophages to osteoclasts, as indicated by tartrate-resistant acid phosphatase (TRAP)-positive cells, and that butein suppressed this process. The chalcone also suppressed the expression of RANKL by the tumor cells. We further found that butein suppressed RANKL-induced NF-κB activation and that this suppression correlated with the inhibition of IκBα kinase and suppression of phosphorylation and degradation of IκBα, an inhibitor of NF-κB. Finally, butein also suppressed the RANKL-induced differentiation of macrophages to osteoclasts in a dose-dependent and time-dependent manner. Collectively, our results indicate that butein suppresses the osteoclastogenesis induced by tumor cells and by RANKL, by suppression of the NF-κB activation pathway.

• Authors: Bokyung Sung, Sung-Gook Cho, Mingyao Liu, Bharat B Aggarwal
• Journal: International journal of cancer (Int J Cancer) Vol. 129 Issue 9 Pg. 2062-72 (Nov 01 2011) ISSN: 1097-0215 [Electronic] United States
• PMID: 21170936 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 UICC.

Chemical References

• Chalcones
• NF-kappa B
• Protein Kinase Inhibitors
• RANK Ligand
• RNA, Messenger
• Receptor Activator of Nuclear Factor-kappa B
• TNF Receptor-Associated Factor 6
• butein
• Matrix Metalloproteinase 9

Topics

• Animals
• Bone Resorption
• Cell Line
• Chalcones (pharmacology)
• Enzyme Activation (drug effects, genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• Matrix Metalloproteinase 9 (genetics)
• Mice
• NF-kappa B (metabolism)
• Neoplasms (genetics, metabolism)
• Osteoclasts (drug effects, metabolism)
• Phosphorylation (drug effects)
• Promoter Regions, Genetic
• Protein Binding (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Protein Stability
• RANK Ligand (antagonists & inhibitors, genetics)
• RNA, Messenger (metabolism)
• Receptor Activator of Nuclear Factor-kappa B (metabolism)
• Signal Transduction (drug effects)
• TNF Receptor-Associated Factor 6 (metabolism)