Get access

Inhibition of matrix metalloproteinase-9 and nuclear factor kappa B contribute to melatonin prevention of motility and invasiveness in HepG2 liver cancer cells

Authors

  • Raquel Ordoñez,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
    2. Institute of Biomedicine (IBIOMED), University of León, León, Spain
    Search for more papers by this author
  • Sara Carbajo-Pescador,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
    2. Institute of Biomedicine (IBIOMED), University of León, León, Spain
    Search for more papers by this author
  • Néstor Prieto-Dominguez,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
    2. Institute of Biomedicine (IBIOMED), University of León, León, Spain
    Search for more papers by this author
  • Andrés García-Palomo,

    1. Institute of Biomedicine (IBIOMED), University of León, León, Spain
    2. Service of Oncology, Hospital of León, Complejo Asistencial Universitario de León, León, Spain
    Search for more papers by this author
  • Javier González-Gallego,

    Corresponding author
    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
    2. Institute of Biomedicine (IBIOMED), University of León, León, Spain
    • Address reprint requests to Javier González-Gallego, Institute of Biomedicine, University of León, 24071-León, Spain.

      E-mail: jgonga@unileon.es

    Search for more papers by this author
  • José L. Mauriz

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain
    2. Institute of Biomedicine (IBIOMED), University of León, León, Spain
    Search for more papers by this author

Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal human cancers worldwide because of its high incidence and its metastatic potential. Extracellular matrix degradation by matrix metalloproteinases (MMPs) has been connected with cancer cell invasion, and it has been suggested that inhibition of MMPs by synthetic and natural inhibitors may be of great importance in the HCC therapies. Melatonin, the main product of the pineal gland, exerts antiproliferative, proapoptotic, and antiangiogenic properties in HepG2 human hepatocellular cells, and exhibits anti-invasive and antimetastatic activities by suppressing the enzymatic activity of MMP-9 in different tumor types. However, the underlying mechanism of anti-invasive activity in HCC models has not been fully elucidated. Here, we demonstrate that 1 mm melatonin dosage reduced in IL-1β-induced HepG2 cells MMP-9 gelatinase activity and inhibited cell invasion and motility through downregulation of MMP-9 gene expression and upregulation of the MMP-9-specific inhibitor tissue inhibitor of metalloproteinases (TIMP)-1. No significant changes were observed in the expression and activity of MMP-2, the other proteinase implicated in matrix collagen degradation, and its tissue inhibitor, TIMP-2. Also, melatonin significantly suppressed IL-1β-induced nuclear factor-kappaB (NF-κB) translocation and transcriptional activity. In summary, we demonstrate that melatonin modulates motility and invasiveness of HepG2 cell in vitro through a molecular mechanism that involves TIMP-1 upregulation and attenuation of MMP-9 expression and activity via NF-κB signal pathway inhibition.

Get access to the full text of this article

Ancillary