TY - JOUR
T1 - IL1 receptor antagonist inhibits pancreatic cancer growth by abrogating NF-κB activation
AU - Zhuang, Zhuonan
AU - Ju, Huai Qiang
AU - Aguilar, Mitzi
AU - Gocho, Takashi
AU - Li, Hao
AU - Iida, Tomonori
AU - Lee, Harold
AU - Fan, Xiaoqiang
AU - Zhou, Haijun
AU - Ling, Jianhua
AU - Li, Zhongkui
AU - Fu, Jie
AU - Wu, Min
AU - Li, Min
AU - Melisi, Davide
AU - Iwakura, Yoichiro
AU - Xu, Kesen
AU - Fleming, Jason B.
AU - Chiao, Paul J.
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2016/3/15
Y1 - 2016/3/15
N2 - Purpose: Constitutive NF-κB activation is identified in about 70% of pancreatic ductal adenocarcinoma (PDAC) cases and is required foroncogenicKRAS-inducedPDACdevelopment inmouse models. We sought to determine whether targeting IL-1α pathway would inhibit NF-κB activity and thus suppress PDAC cell growth. Experimental Design: We determined whether anakinra, a human IL-1 receptor (rhIL-1R) antagonist, inhibited NF-κB activation. Assays for cell proliferation, migration, and invasion were performed with rhIL-1R antagonist using the human PDAC cell lines AsPc1, Colo357, MiaPaCa-2, and HPNE/K-rasG12V/p16sh. In vivo NF-κB activation-dependent tumorigenesis was assayed using an orthotopic nude mouse model (n = 20, 5 per group) treated with a combination of gemcitabine and rhIL-1RA. Results: rhIL-1R antagonist treatment led to a significant decrease in NF-κB activity. PDAC cells treated with rhIL-1R antagonist plus gemcitabine reduced proliferation, migration, and invasion as compared with single gemcitabine treatment. In nude mice, rhIL-1R antagonist plus gemcitabine significantly reduced the tumor burden (gemcitabine plus rhIL-1RA vs. control, P = 0.014). Conclusions: We found that anakinra, an FDA-approved drug that inhibits IL-1 receptor (IL-1R), when given with or without gemcitabine, can reduce tumor growth by inhibiting IL1a-induced NF-κB activity; this result suggests that it is a useful therapeutic approach for PDAC. Clin Cancer Res; 22(6); 1432-44.
AB - Purpose: Constitutive NF-κB activation is identified in about 70% of pancreatic ductal adenocarcinoma (PDAC) cases and is required foroncogenicKRAS-inducedPDACdevelopment inmouse models. We sought to determine whether targeting IL-1α pathway would inhibit NF-κB activity and thus suppress PDAC cell growth. Experimental Design: We determined whether anakinra, a human IL-1 receptor (rhIL-1R) antagonist, inhibited NF-κB activation. Assays for cell proliferation, migration, and invasion were performed with rhIL-1R antagonist using the human PDAC cell lines AsPc1, Colo357, MiaPaCa-2, and HPNE/K-rasG12V/p16sh. In vivo NF-κB activation-dependent tumorigenesis was assayed using an orthotopic nude mouse model (n = 20, 5 per group) treated with a combination of gemcitabine and rhIL-1RA. Results: rhIL-1R antagonist treatment led to a significant decrease in NF-κB activity. PDAC cells treated with rhIL-1R antagonist plus gemcitabine reduced proliferation, migration, and invasion as compared with single gemcitabine treatment. In nude mice, rhIL-1R antagonist plus gemcitabine significantly reduced the tumor burden (gemcitabine plus rhIL-1RA vs. control, P = 0.014). Conclusions: We found that anakinra, an FDA-approved drug that inhibits IL-1 receptor (IL-1R), when given with or without gemcitabine, can reduce tumor growth by inhibiting IL1a-induced NF-κB activity; this result suggests that it is a useful therapeutic approach for PDAC. Clin Cancer Res; 22(6); 1432-44.
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U2 - 10.1158/1078-0432.CCR-14-3382
DO - 10.1158/1078-0432.CCR-14-3382
M3 - Article
C2 - 26500238
AN - SCOPUS:84962209588
SN - 1078-0432
VL - 22
SP - 1432
EP - 1444
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 6
ER -