Antagonism of Inhibitor of Apoptosis Proteins Increases Bone Metastasis via Unexpected Osteoclast Activation
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Abstract
Inhibitor of apoptosis (IAP) proteins play a central role in many types of cancer, and IAP antagonists are in development as anticancer agents. IAP antagonists cause apoptosis in many cells, but they also activate alternative NF-κB signaling through NF-κB–inducing kinase (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, as compared with other sites during IAP antagonist treatment. These drugs also caused osteoporosis and increased osteoclastogenesis, mediated by NIK, and enhanced tumor-associated osteolysis. Cotreatment with zoledronic acid, a potent osteoclast inhibitor, reduced IAP antagonist–enhanced tumor growth in bone and osteolysis. Thus, IAP antagonist–based cancer treatment may be compromised by osteoporosis and enhanced skeletal metastasis, which may be prevented by antiresorptive agents. Significance: Although IAP antagonists are a class of anticancer agents with proven efficacy in multiple cancers, we show that these agents can paradoxically increase tumor growth and metastasis in the bone by stabilizing NIK and activating the alternative NF-κB pathway in osteoclasts. Future clinical trials of IAP antagonist–based therapy may require detailed examination of this potential for enhanced bone metastasis and osteoporosis, as well as possible combination with antiresorptive agents. Cancer Discov; 3(2); 212–23. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 125
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These findings are in line with reported roles for the noncanonical NF-κB pathway in EMT, cellular invasion, and metastasis.
“These findings are in line with reported roles for the noncanonical NF-κB pathway in EMT, cellular invasion, and metastasis33–35.”
From Chromosomal instability drives metastasis through a cytosolic DNA response (2018) · cites this paper as [35]
The Results section ('Osteoclast expression of constitutively active NIK promotes tumor growth in bone'; page unavailable) links activation of the alternative NF-κB pathway in osteoclasts to increased tumor burden in bone. The Discussion likewise describes promotion of metastatic growth through osteoclast activity. These passages support a role in bone metastatic growth, but do not establish roles in EMT or cellular invasion. (LLM, conf=0.85)
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Self-citation
- Authors
- Yang, C., Davis, J. L., Zeng, R., Vora, P., Su, X., Collins, L. I., Vangveravong, S., Mach, R. H., Piwnica-Worms, D., Weilbaecher, K. N., Faccio, R., & Veis Novack, D.
- Affiliations
- Washington University in St. Louis (US)
- Authors' Affiliations: Divisions of 1Bone and Mineral Diseases and 2Molecular Oncology, Department of Medicine; 3Mallinckrodt Institute of Radiology; Departments of 4Cell Biology and Physiology/BRIGHT Institute, 5Orthopedic Surgery, and 6Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
- ORCID
- Venue
- Cancer Discovery
- Published
- 2013-02-01
- Volume
- 3
- Issue
- 2
- Pages
- 212-223
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3570610
- OpenAlex
- W2127166780
- Cited by
- 50
- References
- 48
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 6 · 2019: 1 · 2018: 2 · 2017: 7 · 2016: 5 · 2015: 2 · 2014: 7 · 2013: 9
- FWCI
- 2.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Association for Cancer Research
- Genentech
- National Cancer Institute (R01CA097250, CA-100730, P50 CA94056, P50CA094056, T32CA113275, P01CA100730)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR052705, AR52921, AR53628, P30AR057235, R01AR052705, AR057235, R01AR053628, T32AR060719)
- National Center for Research Resources (S10RR023660)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Oncology › Bone health and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- inhibitor of apoptosis proteins, IAP antagonists, bone metastasis, osteoclast activation, osteoclastogenesis, NF-κB signaling, NIK, osteoporosis, zoledronic acid, antiresorptive agents, drug resistance, bone microenvironment, cancer treatment side effects
- MeSH terms
- Zoledronic Acid, Animals, Antineoplastic Combined Chemotherapy Protocols, Bone and Bones, Bone Neoplasms, Breast Neoplasms, Cells, Cultured, Diphosphonates, Humans, Imidazoles, Macrophages, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Oligopeptides, Osteoclasts, Osteoporosis, Blotting, Western, Molecular Structure, Apoptosis, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Bone Density Conservation Agents, Inhibitor of Apoptosis Proteins, Mice
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