TY - JOUR
T1 - Antagonism of inhibitor of apoptosis proteins increases bone metastasis via unexpected osteoclast activation
AU - Yang, Chang
AU - Davis, Jennifer L.
AU - Zeng, Rong
AU - Vora, Paras
AU - Su, Xinming
AU - Collins, Lynne I.
AU - Vangveravong, Suwanna
AU - Mach, Robert H.
AU - Piwnica-Worms, David
AU - Weilbaecher, Katherine N.
AU - Faccio, Roberta
AU - Novack, Deborah Veis
PY - 2013
Y1 - 2013
N2 - 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 oste-olysis. 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 mul-tiple 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.
AB - 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 oste-olysis. 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 mul-tiple 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.
UR - http://www.scopus.com/inward/record.url?scp=84873915595&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-12-0271
DO - 10.1158/2159-8290.CD-12-0271
M3 - Article
C2 - 23269702
AN - SCOPUS:84873915595
SN - 2159-8274
VL - 3
SP - 212
EP - 223
JO - Cancer discovery
JF - Cancer discovery
IS - 2
ER -