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      Oncogenic Ras induces inflammatory cytokine production by up-regulating the squamous cell carcinoma antigens SerpinB3/B4

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          Abstract

          Mounting evidence indicates that oncogenic Ras can modulate cell autonomous inflammatory cytokine production, although the underlying mechanism remains unclear. Here we show that squamous cell carcinoma antigens 1 and 2 (SCCA1/2), members of the Serpin family of serine/cysteine protease inhibitors, are transcriptionally up-regulated by oncogenic Ras via MAPK and the ETS family transcription factor PEA3. Increased SCCA expression leads to inhibition of protein turnover, unfolded protein response, activation of NF-κB, and is essential for Ras-mediated cytokine production and tumor growth. Analysis of human colorectal and pancreatic tumor samples reveals a positive correlation between Ras mutation, enhanced SCCA expression, and IL-6 expression. These results indicate that SCCA is a Ras-responsive factor that has a role in Ras-associated cytokine production and tumorigenesis.

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          Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion

          Francis Rodier, Jean-Philippe Coppe, Christopher K Patil … (2009)
          Cellular senescence suppresses cancer by stably arresting the proliferation of damaged cells1. Paradoxically, senescent cells also secrete factors that alter tissue microenvironments2. The pathways regulating this secretion are unknown. We show that damaged human cells develop persistent chromatin lesions bearing hallmarks of DNA double-strand breaks (DSBs), which initiate increased secretion of inflammatory cytokines such as interleukin-6 (IL-6). Cytokine secretion occurred only after establishment of persistent DNA damage signaling, usually associated with senescence, not after transient DNA damage responses (DDR). Initiation and maintenance of this cytokine response required the DDR proteins ATM, NBS1 and CHK2, but not the cell cycle arrest enforcers p53 and pRb. ATM was also essential for IL-6 secretion during oncogene-induced senescence and by damaged cells that bypass senescence. Further, DDR activity and IL-6 were elevated in human cancers, and ATM-depletion suppressed the ability of senescent cells to stimulate IL-6-dependent cancer cell invasiveness. Thus, in addition to orchestrating cell cycle checkpoints and DNA repair, a novel and important role of the DDR is to allow damaged cells to communicate their compromised state to the surrounding tissue.
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            Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.

            M. Serrano, A. Lin, M. McCurrach … (1997)
            Oncogenic ras can transform most immortal rodent cells to a tumorigenic state. However, transformation of primary cells by ras requires either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. Here we show that expression of oncogenic ras in primary human or rodent cells results in a permanent G1 arrest. The arrest induced by ras is accompanied by accumulation of p53 and p16, and is phenotypically indistinguishable from cellular senescence. Inactivation of either p53 or p16 prevents ras-induced arrest in rodent cells, and E1A achieves a similar effect in human cells. These observations suggest that the onset of cellular senescence does not simply reflect the accumulation of cell divisions, but can be prematurely activated in response to an oncogenic stimulus. Negation of ras-induced senescence may be relevant during multistep tumorigenesis.
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              Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity.

              Yuchen Chien, Claudio Scuoppo, Xiaowo Wang … (2011)
              Cellular senescence acts as a potent barrier to tumorigenesis and contributes to the anti-tumor activity of certain chemotherapeutic agents. Senescent cells undergo a stable cell cycle arrest controlled by RB and p53 and, in addition, display a senescence-associated secretory phenotype (SASP) involving the production of factors that reinforce the senescence arrest, alter the microenvironment, and trigger immune surveillance of the senescent cells. Through a proteomics analysis of senescent chromatin, we identified the nuclear factor-κB (NF-κB) subunit p65 as a major transcription factor that accumulates on chromatin of senescent cells. We found that NF-κB acts as a master regulator of the SASP, influencing the expression of more genes than RB and p53 combined. In cultured fibroblasts, NF-κB suppression causes escape from immune recognition by natural killer (NK) cells and cooperates with p53 inactivation to bypass senescence. In a mouse lymphoma model, NF-κB inhibition bypasses treatment-induced senescence, producing drug resistance, early relapse, and reduced survival. Our results demonstrate that NF-κB controls both cell-autonomous and non-cell-autonomous aspects of the senescence program and identify a tumor-suppressive function of NF-κB that contributes to the outcome of cancer therapy.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 101528555
                Journal ID (pubmed-jr-id): 37539
                Journal ID (nlm-ta): Nat Commun
                Journal ID (iso-abbrev): Nat Commun
                Title: Nature communications
                ISSN (Electronic): 2041-1723
                Publication date Nihms-submitted: 7 May 2014
                Publication date (Electronic): 23 April 2014
                Publication date Collection: 2014
                Publication date PMC-release: 23 October 2014
                Volume: 5
                Page: 3729
                Affiliations
                [1 ]Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
                [2 ]Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232, USA.
                [3 ]Cancer Genome Center, Cold Spring Harbor Laboratory, Woodbury, New York 11797, USA.
                [4 ]Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida 32224, USA
                Author notes
                [5 ]Corresponding author: Wei-Xing Zong, Department of Molecular Genetics and Microbiology, 216A Life Science Building, Stony Brook University, Stony Brook, New York 11794, USA. Tel.: 631-632-4104; Fax: 631-632-9797; weixing.zong@ 123456stonybrook.edu
                Article
                Manuscript ID: NIHMS579965
                DOI: 10.1038/ncomms4729
                PMC ID: 4025922
                PubMed ID: 24759783
                SO-VID: f524a6f3-0798-42bd-a302-7776675b8fa8
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