The apoptotic pathway triggered by the Fhit protein in lung cancer cell lines is not affected by Bcl-2 or Bcl-x(L) overexpression

Luca Roz, Francesca Andriani, Carlos G. Ferreira, Giuseppe Giaccone, Gabriella Sozzi

Research output: Contribution to journalArticle

Abstract

The expression of the tumour suppressor protein fragile histidine triad (Fhit) is often impaired in many human cancers and its restoration in Fhit-negative cancer cell lines suppresses tumorigenicity and induces apoptosis. Although the proapoptotic function of Fhit is well documented, little is known about its precise mechanism of action and further studies are needed in order to elucidate the putative therapeutic properties of this protein. To this end, we have engineered the lung cancer cell line NCI-H460 in order to express different molecules involved in the control of apoptotic pathways. Infection of these cells with an adenoviral vector transducing the Fhit gene (Ad-Fhit) revealed that complete protection from apoptosis was conferred by the inhibitor of caspases Cytokine response modifier A (CrmA) and by a dominant-negative form of the adapter protein Fas-associated death domain (FADD) and partial protection by a dominant-negative form of caspase-8, while cells over expressing mitoctiondrial mediators of the apoptotic response such as Bcl-2 or Bcl-x(L) that are resistant to treatment with cisplatin, remained highly susceptible to cell death triggered by Fhit gene transfer. In line to what was observed in H460 cells, Ad-Fhit efficacy was not affected by Bcl-2 overexpression also in two other lung cancer cell lines (A549 and Calu-1). Analysis of cytochrome c release also confirmed that in Bcl-2- or Bcl-x(L)-expressing cells apoptosis could be detected by terminal deoxynucleotidyl-transferase mediated dUTP nick-end labelling (TUNEL) assay before any evidence of mitochondrial membrane perturbation. In conclusion, our analysis indicates that the Fhit protein exerts its oncosuppressor activity through induction of an apoptotic mechanism that seems to be FADD dependent, caspase-8 mediated and independent from mitochondrial amplification.

Original languageEnglish
Pages (from-to)9102-9110
Number of pages9
JournalOncogene
Volume23
Issue number56
DOIs
Publication statusPublished - Dec 2 2004

Fingerprint

Histidine
Lung Neoplasms
Cell Line
Caspase 8
Apoptosis
Fas-Associated Death Domain Protein
Tumor Suppressor Proteins
Caspase Inhibitors
DNA Nucleotidylexotransferase
Mitochondrial Membranes
Cytochromes c
fragile histidine triad protein
Cisplatin
Genes
Neoplasms
Cell Death
Cytokines
Infection
Proteins

Keywords

  • Apoptosis control
  • Fhit
  • Lung cancer

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

Cite this

The apoptotic pathway triggered by the Fhit protein in lung cancer cell lines is not affected by Bcl-2 or Bcl-x(L) overexpression. / Roz, Luca; Andriani, Francesca; Ferreira, Carlos G.; Giaccone, Giuseppe; Sozzi, Gabriella.

In: Oncogene, Vol. 23, No. 56, 02.12.2004, p. 9102-9110.

Research output: Contribution to journalArticle

Roz, Luca ; Andriani, Francesca ; Ferreira, Carlos G. ; Giaccone, Giuseppe ; Sozzi, Gabriella. / The apoptotic pathway triggered by the Fhit protein in lung cancer cell lines is not affected by Bcl-2 or Bcl-x(L) overexpression. In: Oncogene. 2004 ; Vol. 23, No. 56. pp. 9102-9110.
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