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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageAmerican English
Article number147
JournalCell Death and Disease
Volume10
Issue number3
DOIs
StatePublished - 1 Mar 2019

Bibliographical note

Funding Information:
The original paper (Trapasso, F. et al. Fhit interaction with ferredoxin reductase triggers generation of reactive oxygen species and apoptosis of cancer cells. J. Biol. Chem. 283, 13736–13744 (2008). Retraction in: J. Biol. Chem. 292, 14279 (2017).) on the interaction of Fhit and Fdxr was withdrawn due to errors discovered in several of the figures; the authors believed strongly in the original conclusions, and felt it was important to confirm the findings and publish the new findings, retaining some of the original data plus additional experiments that show the biological importance of the Fhit–Fdxr interaction in the mitochondria, an interaction that takes on new significance with the surge in studies of inhibitors/modulators of elements of the electron transport chain that are highly relevant to cancer treatment. We thank all of the original authors, some of whom are not included in the current paper because the original experiments in which they participated are not included in the current paper. We are grateful to Bert Vogelstein for providing us with HCT116 FDXR +/–/– and parental cells. This work was supported by grants from the National Institutes of Health; DG Cheung was funded by NIH-NIGMS Grant T32-GM086252 and the OSU/HHMI Med into Grad Scholars Program; Dongju Park is funded by an OSUCCC Pelotonia Postdoctoral fellowship; Teresa Druck is supported by NCI-R35-CA-197706 (to C.M.C.); the Aqeilan lab is supported by the European Research Council (ERC)-Consolidator Grant under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 682118).

Publisher Copyright:
© 2019, The Author(s).

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