alexa Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth.
Oncology

Oncology

Journal of Carcinogenesis & Mutagenesis

Author(s): Houghton AM, Rzymkiewicz DM, Ji H, Gregory AD, Egea EE

Abstract Share this page

Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness. To determine the role of neutrophil elastase (encoded by Elane) on tumor progression, we used the loxP-Stop-loxP K-ras(G12D) (LSL-K-ras) model of mouse lung adenocarcinoma to generate LSL-K-ras-Elane(-/-) mice. Tumor burden was markedly reduced in LSL-K-ras-Elane(-/-) mice at all time points after induction of mutant K-ras expression. Kaplan-Meier survival analysis showed that whereas all LSL-K-ras-Elane(+/+) mice died, none of the mice lacking neutrophil elastase died. Neutrophil elastase directly induced tumor cell proliferation in both human and mouse lung adenocarcinomas by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS-1). Immunoprecipitation studies showed that, as neutrophil elastase degraded IRS-1, there was increased interaction between phosphatidylinositol 3-kinase (PI3K) and the potent mitogen platelet-derived growth factor receptor (PDGFR), thereby skewing the PI3K axis toward tumor cell proliferation. The inverse relationship identified between neutrophil elastase and IRS-1 in LSL-K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS-1 as a key regulator of PI3K within malignant cells. Additionally, to our knowledge, this is the first description of a secreted proteinase gaining access to the inside of a cell and altering intracellular signaling.

This article was published in Nat Med and referenced in Journal of Carcinogenesis & Mutagenesis

Relevant Expert PPTs

Relevant Speaker PPTs

  • Thomas Böldicke
    Intrabodies against the Polysialyltransferases ST8SiaII and ST8SiaIV inhibit Polysialylation of NCAM in rhabdomyosarcoma tumor cells
    PPT Version | PDF Version
  • Hedef Dhafir El-Yassin
    The Immune Response of Prolactin and the Induction of Tumor Necrosis Factor (TNF) in Iraqi Patients Infected with Hepatitis C Virus
    PPT Version | PDF Version
  • Moshe Giladi
    Tumor Treating Fields (TTFields) induced cancer cell death may be immunogenic resulting in enhanced antitumor efficacy when combined with immune-modulating therapy
    PPT Version | PDF Version
  • Ping Yang
    Chronic obstructive pulmonary disease (COPD) complicating early-stage lung cancer (LC)
    PDF Version
  • Al-Said A. Haffor
    Effects of O2 Breathing on the Diaphragm's and the Lungs' Ultra-structural Pathological Changes in Relation to Free Radicals Accumulation
    PDF Version
  • M Shahnawaz Khan
    Graphene Oxide @ Gold Nanorods Conjugate for Controlled Release of Doxorubicin in tumor
    PPT Version | PDF Version
  • Omar E Franco
    Heterogeneous Tumor Stroma and Prostate Carcinogenesis
    PPT Version | PDF Version
  • Yen-Chein Lai
    Molecular pathogenesis in granulosa cell tumor is not only due to somatic FOXL2 mutation
    PPT Version | PDF Version
  • Babak Behnam
    SLUG and SOX9 Cooperatively Regulate Tumor Initiating Niche Factors in Breast Cancer
    PPT Version | PDF Version
  • Yosef Yarden
    Classically, the 3’untranslated region (3’UTR) is that region in eukaryotic protein-coding genes from the translation termination codon to the polyA signal. It is transcribed as an integral part of the mRNA encoded by the gene. However, there exists another kind of RNA, which consists of the 3’UTR alone, without all other elements in mRNA such as 5’UTR and coding region. The importance of independent 3’UTR RNA (referred as I3’UTR) was prompted by results of artificially introducing such RNA species into malignant mammalian cells. Since 1991, we found that the middle part of the 3’UTR of the human nuclear factor for interleukin-6 (NF-IL6) or C/EBP gene exerted tumor suppression effect in vivo. Our subsequent studies showed that transfection of C/EBP 3’UTR led to down-regulation of several genes favorable for malignancy and to up-regulation of some genes favorable for phenotypic reversion. Also, it was shown that the sequences near the termini of the C/EBP 3’UTR were important for its tumor suppression activity. Then, the C/EBP 3’UTR was found to directly inhibit the phosphorylation activity of protein kinase CPKC in SMMC-7721, a hepatocarcinoma cell line. Recently, an AU-rich region in the C/EBP 3’UTR was found also to be responsible for its tumor suppression. Recently we have also found evidence that the independent C/EBP 3’UTR RNA is actually exists in human tissues, such as fetal liver and heart, pregnant uterus, senescent fibroblasts etc. Through 1990’s to 2000’s, world scientists found several 3’UTR RNAs that functioned as artificial independent RNAs in cancer cells and resulted in tumor suppression. Interestingly, majority of genes for these RNAs have promoter-like structures in their 3’UTR regions, although the existence of their transcribed products as independent 3’UTR RNAs is still to be confirmed. Our studies indicate that the independent 3’UTR RNA is a novel non-coding RNA species whose function should be the regulation not of the expression of their original mRNA, but of some essential life activities of the cell as a whole.
    PPT Version | PDF Version
  • Fan-Gang Tseng
    Fan-Gang-Tseng-National-Tsing-Hua-University-Taiwan-Nano-Micro-fluidic-systems-for-circulating-Tumor-Cells-(CTCs)-rapid-detection-and-diagnosis
    PPT Version | PDF Version
  • Myron R Szewczuk
    Therapeutic targeting neuraminidase-1 in multi-stage of tumorigenesis
    PPT Version | PDF Version
  • Hawa ZE Jaafar
    Involvement of elicitated Labisia pumila Benth. biofluids in the alleviation of chemotoxicity effect and antitumor activity
    PPT Version | PDF Version
  • Lourdes Cortes Dericks
    Cancer Stem Cell Markers in Lung Cancer: Proofs of Concept and Some Reservations
    PPT Version | PDF Version
  • Huidi Liu
    Reduced Expression of SOX7 in Ovarian Cancer: a Novel Tumor Suppressor through the Wnt/β-catenin Signaling Pathway
    PPT Version | PDF Version

Recommended Conferences

Peer Reviewed Journals
 
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
 
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

 
© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version
adwords