Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 129, Issue 9, Pages 2062-2072Publisher
WILEY
DOI: 10.1002/ijc.25868
Keywords
butein; RANKL; cancer; osteoclastogenesis; NF-kappa B
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Funding
- Clayton Foundation for Research
- National Institutes of Health [CA-16 672, NIH CA-124787-01A2]
- Center for Targeted Therapy of MD Anderson Cancer Center
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Osteoclastogenesis is associated with aging and various age-related inflammatory chronic diseases, including cancer. Receptor activator of nuclear factor-kappaB (NF-kappa B) 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-kappa B activation and that this suppression correlated with the inhibition of I kappa B alpha kinase and suppression of phosphorylation and degradation of I kappa B alpha, an inhibitor of NF-kappa B. 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-kappa B activation pathway.
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