Anti-cancer IAP Inhibition Increases Bone Metastasis via Unexpected Osteoclast Activation

De:

Yang C, Davis JL, Zeng R, Vora P, Su X, Collins LI, Vangveravong S, Mach RH, Piwnica-Worms D, Weilbaecher KN, Faccio R, Novack DV. Anticancer IAP inhibition increases bone metastasis via unexpected osteoclast activation. Cancer Discovery. February 2013.
This study was supported by the National Institutes of Health (NIH), grant number AR052705, with additional support from AR52921 and AR53628, CA100730, and the Barnes-Jewish Foundation. Histological and microCT analysis was supported in part by the Washington University Center for Musculoskeletal Research NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), grant number AR057235. The Molecular Imaging Center was supported by NIH grant P50 CA94056. Genentech, Inc. provided BV6. 
Cancer Discov. Author manuscript; available in PMC Feb 1, 2014.
Published in final edited form as:
PMCID: PMC3570610
NIHMSID: NIHMS430908
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Abstract

IAP (inhibitor of apoptosis) proteins play a central role in many types of cancer, and IAP antagonists are in development as anti-cancer agents. IAP antagonists cause apoptosis in many cells, but they also activate alternative NF-κB signaling through NIK, which regulates osteoclasts. In bone metastasis, a positive feedback loop between tumors and osteoclasts promotes tumor growth and osteolysis. We therefore tested the effect of IAP antagonists on the bone microenvironment for metastasis. In both drug-sensitive and drug-resistant tumors, growth in bone was favored compared to other sites during IAP antagonist treatment. These drugs also caused osteoporosis and increased osteoclastogenesis, mediated by NIK, and enhanced tumor-associated osteolysis. Co-treatment with zoledronic acid, a potent osteoclast inhibitor, reduced IAP antagonist-enhanced tumor growth in bone and osteolysis. Thus, IAP-based cancer treatment may be compromised by osteoporosis and enhanced skeletal metastasis which may be prevented by anti-resorptive agents.
Keywords: bone metastasis, IAP antagonist, osteoclast, NF-κB, NIK


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