Fhit interaction with ferredoxin reductase triggers generation of reactive oxygen species and apoptosis of cancer cells.
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.
Trapasso
Francesco
F
Ohio State University, Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
Pichiorri
Flavia
F
Gaspari
Marco
M
Palumbo
Tiziana
T
Aqeilan
Rami I
RI
Gaudio
Eugenio
E
Okumura
Hiroshi
H
Iuliano
Rodolfo
R
Di Leva
Giampiero
G
Fabbri
Muller
M
Birk
David E
DE
Raso
Cinzia
C
Green-Church
Kari
K
Spagnoli
Luigi G
LG
Venuta
Salvatore
S
Huebner
Kay
K
Croce
Carlo M
CM
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
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