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

  • Druck T Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA.
  • Cheung DG Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA.
  • Park D Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA.
  • Trapasso F Dipartimento di Medicina Sperimentale e Clinica, University "Magna Græcia" of Catanzaro, Catanzaro, 88100, Italy.
  • Pichiorri F Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope, Duarte, CA, USA.
  • Gaspari M Dipartimento di Medicina Sperimentale e Clinica, University "Magna Græcia" of Catanzaro, Catanzaro, 88100, Italy.
  • Palumbo T Dipartimento di Farmacologia Sperimentale Preclinica e Clinica, University of Catania, Catania, 95123, Italy.
  • Aqeilan RI Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA.
  • Gaudio E Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
  • Okumura H Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medical Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan.
  • Iuliano R Dipartimento di Medicina Sperimentale e Clinica, University "Magna Græcia" of Catanzaro, Catanzaro, 88100, Italy.
  • Raso C Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Dublin, Ireland.
  • Green K Department of Chemistry, Mass Spectrometry Research and Education Center, University of Florida, 126 Sisler Hall, Gainesville, FL, 32611-7200, USA.
  • Huebner K Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA.
  • Croce CM Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA. Carlo.Croce@osumc.edu.
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  • 2019-02-17
Published in:
  • Cell death & disease. - 2019
A549 Cells
Acid Anhydride Hydrolases
Apoptosis
Atovaquone
Cell Survival
Chaperonin 10
Chaperonin 60
Colonic Neoplasms
Ferredoxin-NADP Reductase
HCT116 Cells
Humans
Lung Neoplasms
Mitochondria
Mitochondrial Proteins
Neoplasm Proteins
Oxidative Phosphorylation
Reactive Oxygen Species
Transfection
English 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.
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  • English
Open access status
gold
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https://sonar.ch/global/documents/112400
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