title: Fhit interaction with ferredoxin reductase triggers generation of reactive oxygen species and apoptosis of cancer cells.
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.
authors.affiliation: Ohio State University, Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Trapasso
authors.forename: Flavia
authors.initials: F
authors.lastname: Pichiorri
authors.forename: Marco
authors.initials: M
authors.lastname: Gaspari
authors.forename: Tiziana
authors.initials: T
authors.lastname: Palumbo
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okumura
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Iuliano
authors.forename: Giampiero
authors.initials: G
authors.lastname: Di Leva
authors.forename: Muller
authors.initials: M
authors.lastname: Fabbri
authors.forename: David E
authors.initials: DE
authors.lastname: Birk
authors.forename: Cinzia
authors.initials: C
authors.lastname: Raso
authors.forename: Kari
authors.initials: K
authors.lastname: Green-Church
authors.forename: Luigi G
authors.initials: LG
authors.lastname: Spagnoli
authors.forename: Salvatore
authors.initials: S
authors.lastname: Venuta
authors.forename: Kay
authors.initials: K
authors.lastname: Huebner
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000378:metabolism*; D017209:Apoptosis; D045744:Cell Line, Tumor; D018835:Chaperonin 10 / Q000737:chemistry; D018834:Chaperonin 60 / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism; D004249:DNA Damage; D050900:Ferredoxin-Nitrite Reductase / Q000737:chemistry*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D011485:Protein Binding; D017382:Reactive Oxygen Species; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D018835:Chaperonin 10; D018834:Chaperonin 60; D050900:Ferredoxin-Nitrite Reductase; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D000099170:Bis(5'-adenosyl)triphosphatase