Fhit-Fdxr interaction in the mitochondria: modulation of reactive oxygen species generation and apoptosis in cancer cells.

Abstract

Fhit protein is lost in cancers of most, perhaps all, cancer types; when restored, it can induce apoptosis and suppress tumorigenicity, as shown in vitro and in mouse tumor models in vivo. Following protein cross-linking and proteomics analyses, we characterized a Fhit protein complex involved in triggering Fhit-mediated apoptosis. The complex includes the heat-shock chaperonin pair, HSP60/10, which is likely involved in importing Fhit into the mitochondria, where it interacts with ferredoxin reductase, responsible for transferring electrons from NADPH to cytochrome P450 via ferredoxin, in electron transport chain complex III. Overexpression of Fhit protein in Fhit-deficient cancer cells modulates the production of intracellular reactive oxygen species, causing increased ROS, following peroxide treatment, with subsequent increased apoptosis of lung cancer cells under oxidative stress conditions; conversely, Fhit-negative cells escape ROS overproduction and ROS-induced apoptosis, likely carrying oxidative damage. Thus, characterization of Fhit-interacting proteins has identified direct effectors of a Fhit-mediated apoptotic signal pathway that is lost in many cancers. This is of translational interest considering the very recent emphasis in a number of high-profile publications, concerning the role of oxidative phosphorylation in the treatment of human cancers, and especially cancer stem cells that rely upon oxidative phosphorylation for survival. Additionally, we have shown that cells from a Fhit-deficient lung cancer cell line, are sensitive to killing by exposure to atovaquone, thought to act as a selective oxidative phosphorylation inhibitor by targeting the CoQ10 dependence of the mitochondrial complex III, while the Fhit-expressing sister clone is resistant to this treatment.

• Authors: Teresa Druck, Douglas G Cheung, Dongju Park, Francesco Trapasso, Flavia Pichiorri, Marco Gaspari, Tiziana Palumbo, Rami I Aqeilan, Eugenio Gaudio, Hiroshi Okumura, Rodolfo Iuliano, Cinzia Raso, Kari Green, Kay Huebner, Carlo M Croce
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 3 Pg. 147 (02 15 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 30770797 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chaperonin 10
• Chaperonin 60
• HSPD1 protein, human
• Mitochondrial Proteins
• Neoplasm Proteins
• Reactive Oxygen Species
• fragile histidine triad protein
• Ferredoxin-NADP Reductase
• Acid Anhydride Hydrolases
• Atovaquone

Topics

• A549 Cells
• Acid Anhydride Hydrolases (genetics, metabolism)
• Apoptosis (genetics)
• Atovaquone (pharmacology)
• Cell Survival (drug effects, genetics)
• Chaperonin 10 (metabolism)
• Chaperonin 60 (metabolism)
• Colonic Neoplasms (metabolism, pathology)
• Ferredoxin-NADP Reductase (metabolism)
• HCT116 Cells
• Humans
• Lung Neoplasms (metabolism, pathology)
• Mitochondria (metabolism)
• Mitochondrial Proteins (metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Oxidative Phosphorylation (drug effects)
• Reactive Oxygen Species (metabolism)
• Transfection