Restoration of fragile histidine triad (FHIT) expression induces apoptosis and suppresses tumorigenicity in lung and cervical cancer cell lines

Luca Roz, Marcella Gramegna, Hideshi Ishii, Carlo M. Croce, Gabriella Sozzi

Research output: Contribution to journalArticle

Abstract

Loss of expression of the Fhit protein is often associated with the development of many human epithelial cancers, including lung and cervical carcinomas. Restoration of Fhit expression in cell lines derived from these tumors has however yielded conflicting results, prompting the need for careful evaluation of the oncosuppressive potential of FHIT. In the present study, we have investigated the effect of Fhit reintroduction in seven lung cancer and three cervical cancer cell lines. To achieve efficient gene transfer and high levels of transgene expression, we have used an adenoviral vector to transduce the FHIT gene. The induction of apoptosis was evaluated by using the terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay and propidium iodide staining. Activation of caspases was detected by using Western blot analysis, and tumorigenic potential of transduced cells in the nude mouse was also assessed. Restoration of Fhit expression induced apoptosis in all Fhit-negative cell lines, with Calu-1, H460, and A549 being the most susceptible among the lung cancer cell lines and SiHa cells among cervical carcinomas. Activation of caspase-8 was always associated with Fhit-mediated apoptosis, and in vivo tumorigenicity was either abolished by FHIT gene transfer (in H460 and SK-Mes cells) or strongly suppressed (in A549 and SiHa cells). Our data demonstrate oncosuppressive properties and strong proapoptotic activity of the Fhit protein in lung and cervical cancer cell lines and strengthens the hypothesis of its possible use as a therapeutic tool.

Original languageEnglish
Pages (from-to)3615-3620
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number6
DOIs
Publication statusPublished - Mar 19 2002

Keywords

  • Gene therapy
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Genetics
  • General

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