Inhibition of metalloproteinase activity in FANCA is linked to altered oxygen metabolism

J Cell Physiol. 2015 Mar;230(3):603-9. doi: 10.1002/jcp.24778.

Abstract

Bone marrow (BM) failure, increased risk of myelodysplastic syndrome, acute leukaemia and solid tumors, endocrinopathies and congenital abnormalities are the major clinical problems in Fanconi anemia patients (FA). Chromosome instability and DNA repair defects are the cellular characteristics used for the clinical diagnosis. However, these biological defects are not sufficient to explain all the clinical phenotype of FA patients. The known defects are structural alteration in cell cytoskeleton, altered structural organization for intermediate filaments, nuclear lamina, and mitochondria. These are associated with different expression and/or maturation of the structural proteins vimentin, mitofilin, and lamin A/C suggesting the involvement of metalloproteinases (MPs). Matrix metalloproteinases (MMP) are involved in normal physiological processes such as human skeletal tissue development, maturation, and hematopoietic reconstitution after bone marrow suppression. Current observations upon the eventual role of MPs in FA cells are largely inconclusive. We evaluated the overall MPs activity in FA complementation group A (FANCA) cells by exposing them to the antioxidants N-acetyl cysteine (NAC) and resveratrol (RV). This work supports the hypothesis that treatment of Fanconi patients with antioxidants may be important in FA therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / administration & dosage
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Chromosomal Instability / genetics
  • DNA Repair / genetics
  • DNA-Binding Proteins
  • Fanconi Anemia / drug therapy
  • Fanconi Anemia / metabolism*
  • Fanconi Anemia / pathology
  • Female
  • Humans
  • Metalloproteases / antagonists & inhibitors
  • Metalloproteases / metabolism*
  • Mitochondrial Proteins / metabolism
  • Muscle Proteins / metabolism
  • Muscle, Skeletal / growth & development*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Oxygen / metabolism*
  • Vimentin / metabolism

Substances

  • Antioxidants
  • DNA-Binding Proteins
  • IMMT protein, human
  • Mitochondrial Proteins
  • Muscle Proteins
  • Vimentin
  • Metalloproteases
  • Oxygen