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IL1 Receptor Antagonist Inhibits Pancreatic Cancer Growth by Abrogating NF-?B Activation.

ABSTRACT: PURPOSE:Constitutive NF-?B activation is identified in about 70% of pancreatic ductal adenocarcinoma (PDAC) cases and is required for oncogenic KRAS-induced PDAC development in mouse models. We sought to determine whether targeting IL-1? pathway would inhibit NF-?B activity and thus suppress PDAC cell growth. EXPERIMENTAL DESIGN:We determined whether anakinra, a human IL-1 receptor (rhIL-1R) antagonist, inhibited NF-?B 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-ras(G12V)/p16sh. In vivo NF-?B 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-?B 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 IL1?-induced NF-?B activity; this result suggests that it is a useful therapeutic approach for PDAC.

SUBMITTER: Zhuang Z

PROVIDER: S-EPMC6437768 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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IL1 Receptor Antagonist Inhibits Pancreatic Cancer Growth by Abrogating NF-κB Activation.

Zhuang Zhuonan Z Ju Huai-Qiang HQ Aguilar Mitzi M Gocho Takashi T Li Hao H Iida Tomonori T Lee Harold H Fan Xiaoqiang X Zhou Haijun H Ling Jianhua J Li Zhongkui Z Fu Jie J Wu Min M Li Min M Melisi Davide D Iwakura Yoichiro Y Xu Kesen K Fleming Jason B JB Chiao Paul J PJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20151023 6

<h4>Purpose</h4>Constitutive NF-κB activation is identified in about 70% of pancreatic ductal adenocarcinoma (PDAC) cases and is required for oncogenic KRAS-induced PDAC development in mouse models. We sought to determine whether targeting IL-1α pathway would inhibit NF-κB activity and thus suppress PDAC cell growth.<h4>Experimental design</h4>We determined whether anakinra, a human IL-1 receptor (rhIL-1R) antagonist, inhibited NF-κB activation. Assays for cell proliferation, migration, and inva ...[more]

PMID: 26500238

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Project description:BACKGROUND:Interleukin-1 alpha (IL-1?) plays an important role in tumorigenesis and angiogenesis of gastric cancer. The interleukin-1 receptor antagonist (IL-1RA) inhibits IL-1 selectively and specifically through IL-1R type I (IL-1RI). However, the underlying mechanism by which IL-1RA modulates the interactions of tumor cells and their micro-environment is poorly understood. We have evaluated the role of IL-1RA in the metastatic process as well as the mutual or reciprocal actions between gastric cancer cells and stromal cells. MATERIALS AND METHODS:The expressions of IL-1?, vascular endothelial growth factor (VEGF), and IL-1RI mRNA were determined by reverse transcriptase-PCR. The regulatory effect of IL-1RA on the secretion of VEGF in human gastric cancer cells and human umbilical vein endothelial cells (HUVECs) was detected by enzyme-linked immunosorbent assay. The effect of IL-1RA on metastatic potential was evaluated using proliferation, invasion, and angiogenesis assays, respectively, including in vitro co-culture system models consisting of tumor cells and stromal cells that were used to detect invasion and angiogenesis. RESULTS:Interleukin-1? mRNA was detected in the higher liver metastatic gastric cell line MKN45. IL-1? protein was expressed in MKN45 cells and in HUVECs. VEGF mRNA and protein were detected in the three gastric cancer cell lines (MKN4, NUGC-4, and AGS). Levels of VEGF secreted by gastric cancer cells and HUVECs appeared to be reduced through the action of IL-1RA via IL-1RI in a dose-dependent manner (P < 0.01). IL-1RA significantly inhibited the proliferation and migration of HUVECs (P < 0.01) and tube formation by HUVECs (P < 0.01), both in a dose-dependent manner. Compared with HUVECs grown without cancer cells (control) or with NUGC-4 cells, tube formation by HUVECs was significantly enhanced by co-culture with MKN45 cells (P < 0.01). The enhanced tube formation in the presence of MKN45 cells was inhibited by the addition of IL-1RA (P < 0.01). CONCLUSIONS:The IL-1RA downregulated the metastatic potential of gastric cancer through blockage of the IL-1?/VEGF signaling pathways. IL-1RA has the potential to play a role in the treatment of gastric cancer.

Dataset Information

IL1 Receptor Antagonist Inhibits Pancreatic Cancer Growth by Abrogating NF-?B Activation.

Publications

IL1 Receptor Antagonist Inhibits Pancreatic Cancer Growth by Abrogating NF-κB Activation.

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