Fhit interaction with ferredoxin reductase triggers generation of reactive oxygen species and apoptosis of cancer cells

Francesco Trapasso, Flavia Pichiorri, Marco Gaspari, Tiziana Palumbo, Rami I. Aqeilan, Eugenio Gaudio, Hiroshi Okumura, Rodolfo Iuliano, Giampiero Di Leva, Muller Fabbri, David E. Birk, Cinzia Raso, Kari Green-Church, Luigi G. Spagnoli, Salvatore Venuta, Kay Huebner, Carlo M. Croce

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Fhit protein is lost in most cancers, its restoration suppresses tumorigenicity, and virus-mediated FHIT gene therapy induces apoptosis and suppresses tumors in preclinical models. We have used protein cross-linking and proteomics methods to characterize a Fhit protein complex involved in triggering Fhit-mediated apoptosis. The complex includes Hsp60 and Hsp10 that mediate Fhit stability and may affect import into mitochondria, where it interacts with ferredoxin reductase, responsible for transferring electrons from NADPH to cytochrome P450 via ferredoxin. Viral-mediated Fhit restoration increases production of intracellular reactive oxygen species, followed by increased apoptosis of lung cancer cells under oxidative stress conditions; conversely, Fhit-negative cells escape apoptosis, carrying serious oxidative DNA damage that may contribute to an increased mutation rate. Characterization of Fhit interacting proteins has identified direct effectors of the Fhit-mediated apoptotic pathway that is lost in most cancers through loss of Fhit.

Original languageAmerican English
Pages (from-to)13736-13744
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number20
DOIs
StatePublished - 16 May 2008
Externally publishedYes

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