Cathepsin L in tumor angiogenesis and its therapeutic intervention by the small molecule inhibitor KGP94 View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-04-07

AUTHORS

Dhivya R. Sudhan, Maria B. Rabaglino, Charles E. Wood, Dietmar W. Siemann

ABSTRACT

A significant proportion of breast cancer patients harbor clinically undetectable micrometastases at the time of diagnosis. If left untreated, these micro-metastases may lead to disease relapse and possibly death. Hence, there is significant interest in the development of novel anti-metastatic agents that could also curb the growth of pre-established micrometastases. Like primary tumor, the growth of metastases also is driven by angiogenesis. Although the role of cysteine protease Cathepsin L (CTSL) in metastasis associated tumor cell functions such as migration and invasion is well recognized, its role in tumor angiogenesis remains less explored. The present study examines the contribution of CTSL to breast cancer angiogenesis and evaluates the anti-angiogenic efficacy of CTSL inhibitor KGP94. CTSL semi-quantitative RT-PCR analysis on breast tissue panels revealed significant upregulation of CTSL in breast cancer patients which strongly correlated with increased relapse and metastatic incidence and poor overall survival. Preclinically, CTSL ablation using shRNA or KGP94 treatment led to a significant reduction in MDA-MB-231 tumor cell induced angiogenesis in vivo. In-vitro assessments demonstrated a significant decrease in various angiogenic properties such as endothelial cell sprouting, migration, invasion, tube formation and proliferation in the presence of KGP94. Microarray analyses revealed a significant upregulation of cell cycle related genes by CTSL. Western blot analyses further confirmed upregulation of members of the cyclin family by CTSL. Collectively, these data indicate that CTSL is an important contributor to tumor angiogenesis and that the CTSL inhibition may have therapeutic utility in the treatment of breast cancer patients. More... »

PAGES

461-473

References to SciGraph publications

  • 2010-03-11. In vitro angiogenesis: endothelial cell tube formation on gelled basement membrane extract in NATURE PROTOCOLS
  • 2009-12-18. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients in BREAST CANCER RESEARCH AND TREATMENT
  • 2004-05-03. Inhibition of cathepsin B and MMP-9 gene expression in glioblastoma cell line via RNA interference reduces tumor cell invasion, tumor growth and angiogenesis in ONCOGENE
  • 2008-07-11. Intratumoral gene delivery of anti-cathepsin L single-chain variable fragment by lentiviral vector inhibits tumor progression induced by human melanoma cells in CANCER GENE THERAPY
  • 2013-06-09. Cathepsin L inhibition by the small molecule KGP94 suppresses tumor microenvironment enhanced metastasis associated cell functions of prostate and breast cancer cells in CLINICAL & EXPERIMENTAL METASTASIS
  • 2005-01-23. Cathepsin L is required for endothelial progenitor cell–induced neovascularization in NATURE MEDICINE
  • 2010-06-22. Cathepsins B and L in peripheral blood mononuclear cells of pediatric acute myeloid leukemia: potential poor prognostic markers in ANNALS OF HEMATOLOGY
  • 2011-02-24. Cathepsin L derived from skeletal muscle cells transfected with bFGF promotes endothelial cell migration in EXPERIMENTAL & MOLECULAR MEDICINE
  • 2009-09-22. Monitoring compartment-specific substrate cleavage by cathepsins B, K, L, and S at physiological pH and redox conditions in BMC MOLECULAR AND CELL BIOLOGY
  • 2009-12-21. Deficiency for the cysteine protease cathepsin L promotes tumor progression in mouse epidermis in ONCOGENE
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s10585-016-9790-1

    DOI

    http://dx.doi.org/10.1007/s10585-016-9790-1

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1044265321

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/27055649


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    132 time of diagnosis
    133 tissue panel
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    135 tube formation
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