• Corpus ID: 30707958

IL 1 Receptor Antagonist Inhibits Pancreatic Cancer Growth by Abrogating NFk B Activation

@inproceedings{Zhuang2016IL1R,
  title={IL 1 Receptor Antagonist Inhibits Pancreatic Cancer Growth by Abrogating NFk B Activation},
  author={Zhuo-nan Zhuang and Huai-qiang Ju and Mitzi Aguilar and Takashi Gocho and Hao Li and Tomonori Iida and Harold Lee and Xiaoqiang Fan and Haijun Zhou and Jianhua Ling and Zhongkui Li and Jie Fu and Min Wu and Min Li and Davide Melisi and Yoichiro Iwakura and Kesen Xu and Jason B. Fleming and Paul J. Chiao},
  year={2016}
}

• Z. Zhuang, Huai-qiang Ju, +16 authors P. Chiao
• Published 2016
• Biology, Medicine

Purpose: Constitutive NF-kB 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-1a pathway would inhibit NF-kB activity and thus suppress PDAC cell growth. Experimental Design: We determined whether anakinra, a human IL-1 receptor (rhIL-1R) antagonist, inhibited NF-kB activation. Assays for cell proliferation, migration, and invasion were performed with rhIL-1R antagonist using the human PDAC cell linesAsPc1, Colo357,MiaPaCa-2, andHPNE/K-ras/p16sh. In vivo NF-kB activation–dependent tumorigenesis was assayed using an orthotopic nude mouse model (n 1⁄4 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-kB 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 tumorburden (gemcitabine plus rhIL-1RAvs. control, P 1⁄4 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-kB activity; this result suggests that it is a useful therapeutic approach for PDAC. Clin Cancer Res; 1–13. 2015 AACR. Introduction Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States (1, 2). Mutational activation of KRAS is detected in almost 90% of PDAC cases (2). Recent studies have shown that mutant KRAS is required not only for the initiation of PDAC but also for maintaining the tumorigenic phenotype (3, 4). We previously identified the KRAS-induced constitutive NF-kB in PDAC cells and patient samples (5, 6). Our recent study demonstrated that NF-kB activation is required for mutant KRAS to induce PDAC (6). As targeting mutant RAS proteins directly with small-molecule inhibitors has so far proved unsuccessful, one of the ideas is to identify key signaling pathways that function downstream of RAS and that inhibiting such signaling pathways may lead to tumor suppression (7, 8). NF-kB represents an important signaling pathway that is required by mutant KRAS in PDAC development (6). NF-kB transcription factors are involved in the regulation of cell proliferation, apoptosis, and inflammatory responses and in the stimulation of invasion and metastasis to promote multiple aspects of cancer development and progression (9). Some of the proinflammatory factors, such as IL-1 and TNFa, are regulated by NF-kB, also potent inducers of NF-kB, and strongly associated with most types of PDAC (10). For example, we showed that oncogenic KRAS activates NF-kB constitutively through the IL-1a autocrine mechanism in vivo (6), and overexpression of EGFR in PDAC induced IL-1a expression through AP-1 activity (10). Autocrine stimulation of IL-1a induced the constitutive activation of NF-kB (11). Furthermore, a number of chemotherapy agents, such as gemcitabine, a standard of care for PDAC (12), are able to activate NF-kB in pancreatic cancer cells and result in chemoresistance. Thus, NF-kB has been proposed as a target for PDAC. NF-kB inhibitionwithnonspecific or specific inhibitors, such as glucocorticoids, natural products, is an attractive approach to cancer treatment (13). NEMO (IKKg) or NF-kB essential modulator (NEMO) is a target that can be blocked by a cell-permeable Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of General Surgery, Beijing Tsinghua Changgung Hospital Medical Center,TsinghuaUniversity, Beijing, China. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. Department of Surgery, Jikei University School of Medicine, Tokyo, Japan. Department of Surgery, The University of Oklahoma Health Sciences Center, Stanton L.Young Biomedical Research Center, Oklahoma City, Oklahoma. Digestive Molecular Clinical Oncology Research Unit, Universit a degli studi di Verona, Verona, Italy. Center for Experimental Medicine and Systems Biology, Institute of Medical Science,University of Tokyo,Minato-ku,Tokyo, Japan. Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, China. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Cancer Biology Program, the University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Z. Zhuang and H. Ju contributed equally to this article. Corresponding Author: Paul J. Chiao, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: [phone]; Fax: [phone]; E-mail: [e-mail] doi: 10.1158/1078-0432.CCR-14-3382 2015 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org OF1 Research. on July 15, 2017. © 2015 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst October 23, 2015; DOI: 10.1158/1078-0432.CCR-14-3382