Induction of apoptosis by tumor suppressor FHIT via death receptor signaling pathway in human lung cancer cells

Biochem Biophys Res Commun. 2007 Apr 20;355(4):993-9. doi: 10.1016/j.bbrc.2007.02.067. Epub 2007 Feb 22.


FHIT is a novel tumor suppressor gene located at human chromosome 3p14.2. Restoration of wild-type FHIT in 3p14.2-deficient human lung cancer cells inhibits cell growth and induces apoptosis. In this study, we analyzed potential upstream/downstream molecular targets of the FHIT protein and found that FHIT specifically targeted and regulated death receptor (DR) genes in human non-small-cell lung cancer (NSCLC) cells. Exogenous expression of FHIT by a recombinant adenoviral vector (Ad)-mediated gene transfer upregulated expression of DR genes. Treatment with a recombinant TRAIL protein, a DR-specific ligand, in Ad-FHIT-transduced NSCLC cells considerably enhanced FHIT-induced apoptosis, further demonstrating the involvement of DRs in FHIT-induced apoptosis. Moreover, we also found that FHIT targeted downstream of the DR-mediated signaling pathway. FHIT overexpression disrupted mitochondrial membrane integrity and activated multiple pro-apoptotic proteins in NSCLC cell. These results suggest that FHIT induces apoptosis through a sequential activation of DR-mediated pro-apoptotic signaling pathways in human NSCLC cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acid Anhydride Hydrolases / genetics
  • Acid Anhydride Hydrolases / metabolism*
  • Apoptosis*
  • Caspases / metabolism
  • Enzyme Activation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Ligands
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology*
  • Mitochondrial Membranes / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Receptors, Death Domain / genetics
  • Receptors, Death Domain / metabolism*
  • Signal Transduction*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation


  • Ligands
  • Neoplasm Proteins
  • Receptors, Death Domain
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Suppressor Proteins
  • fragile histidine triad protein
  • Caspases
  • Acid Anhydride Hydrolases