title: Antagonism of inhibitor of apoptosis proteins increases bone metastasis via unexpected osteoclast activation.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Chang
authors.initials: C
authors.lastname: Yang
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Davis
authors.forename: Rong
authors.initials: R
authors.lastname: Zeng
authors.forename: Paras
authors.initials: P
authors.lastname: Vora
authors.forename: Xinming
authors.initials: X
authors.lastname: Su
authors.forename: Lynne I
authors.initials: LI
authors.lastname: Collins
authors.forename: Suwanna
authors.initials: S
authors.lastname: Vangveravong
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Weilbaecher
authors.forename: Roberta
authors.initials: R
authors.lastname: Faccio
authors.forename: Deborah Veis
authors.initials: DV
authors.lastname: Novack
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004164:Diphosphonates / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D015394:Molecular Structure; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010024:Osteoporosis / Q000139:chemically induced / Q000517:prevention & control; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: C582180:BV6 peptide; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; D000077211:Zoledronic Acid