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      Reduced cell proliferation by IKK2 depletion in a mouse lung cancer model

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          Abstract

          Lung cancer is one of the leading cancer malignancies with a five-year survival rate of only ~15%. We have developed a lentiviral vector mediated mouse model which allows generation of non-small cell lung cancer from less than one hundred alveolar epithelial cells, and investigated the role of IKK2 and NF-κB in lung cancer development. IKK2 depletion in tumour cells significantly attenuated tumour proliferation and significantly prolonged mouse survival. We identified Timp-1, one of the NF-κB target genes, as a key mediator for tumour growth. Activation of Erk signalling pathway and cell proliferation requires Timp-1 and its receptor CD63. Knockdown of either IKK2 or Timp-1 by shRNAs reduced tumour growth in both xenograft and lentiviral models. Our results, thus suggest the possible application of IKK2 and Timp-1 inhibitors in treating lung cancer.

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          Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls.

          Véronique Baud, Michael Karin (2009)
          Nuclear factor kappaB (NF-kappaB) transcription factors have a key role in many physiological processes such as innate and adaptive immune responses, cell proliferation, cell death, and inflammation. It has become clear that aberrant regulation of NF-kappaB and the signalling pathways that control its activity are involved in cancer development and progression, as well as in resistance to chemotherapy and radiotherapy. This article discusses recent evidence from cancer genetics and cancer genome studies that support the involvement of NF-kappaB in human cancer, particularly in multiple myeloma. The therapeutic potential and benefit of targeting NF-kappaB in cancer, and the possible complications and pitfalls of such an approach, are explored.
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            NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta.

            Florian Greten, Melek Arkan, Julia Bollrath … (2007)
            IKKbeta-dependent NF-kappaB activation plays a key role in innate immunity and inflammation, and inhibition of IKKbeta has been considered as a likely anti-inflammatory therapy. Surprisingly, however, mice with a targeted IKKbeta deletion in myeloid cells are more susceptible to endotoxin-induced shock than control mice. Increased endotoxin susceptibility is associated with elevated plasma IL-1beta as a result of increased pro-IL-1beta processing, which was also seen upon bacterial infection. In macrophages enhanced pro-IL-1beta processing depends on caspase-1, whose activation is inhibited by NF-kappaB-dependent gene products. In neutrophils, however, IL-1beta secretion is caspase-1 independent and depends on serine proteases, whose activity is also inhibited by NF-kappaB gene products. Prolonged pharmacologic inhibition of IKKbeta also augments IL-1beta secretion upon endotoxin challenge. These results unravel an unanticipated role for IKKbeta-dependent NF-kappaB signaling in the negative control of IL-1beta production and highlight potential complications of long-term IKKbeta inhibition.
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              Tobacco smoke promotes lung tumorigenesis by triggering IKKbeta- and JNK1-dependent inflammation.

              Hiroyuki Takahashi, Hisanobu Ogata, Reiko Nishigaki … (2010)
              Chronic exposure to tobacco smoke, which contains over 60 tumor-initiating carcinogens, is the major risk factor for development of lung cancer, accounting for a large portion of cancer-related deaths worldwide. It is well established that tobacco smoke is a tumor initiator, but we asked whether it also acts as a tumor promoter once malignant initiation, such as caused by K-ras activation, has taken place. Here we demonstrate that repetitive exposure to tobacco smoke promotes tumor development both in carcinogen-treated mice and in transgenic mice undergoing sporadic K-ras activation in lung epithelial cells. Tumor promotion is due to induction of inflammation that results in enhanced pneumocyte proliferation and is abrogated by IKKbeta ablation in myeloid cells or inactivation of JNK1. Copyright (c) 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100890575
                Journal ID (pubmed-jr-id): 21417
                Journal ID (nlm-ta): Nat Cell Biol
                Journal ID (iso-abbrev): Nat. Cell Biol.
                Title: Nature cell biology
                ISSN (Print): 1465-7392
                ISSN (Electronic): 1476-4679
                Publication date Nihms-submitted: 5 January 2012
                Publication date (Electronic): 12 February 2012
                Publication date PMC-release: 01 September 2012
                Volume: 14
                Issue: 3
                Pages: 257-265
                Affiliations
                [1 ]Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
                [2 ]Graduate Program in Bioinformatics, University of California San Diego, La Jolla California 92093, USA
                [3 ]Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
                [4 ]Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
                [5 ]Molecular and Cellular Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
                [6 ]Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
                Author notes
                Correspondence should be addressed to I.M.V. Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA verma@ 123456salk.edu . Phone: +1 858-453-4100 x1462. Fax: +1 858-558-7454.
                Article
                Manuscript ID: nihpa347541
                DOI: 10.1038/ncb2428
                PMC ID: 3290728
                PubMed ID: 22327365
                SO-VID: 52d558f0-2297-4254-bc0e-60618a77508c
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI048034-13 || AI
                Categories
                Subject: Article

                ScienceOpen disciplines: Cell biology
                Data availability:
                ScienceOpen disciplines: Cell biology

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