title: Activation of apoptosis in NAF-1-deficient human epithelial breast cancer cells.
abstract: Maintaining iron (Fe) ion and reactive oxygen species homeostasis is essential for cellular function, mitochondrial integrity and the regulation of cell death pathways, and is recognized as a key process underlying the molecular basis of aging and various diseases, such as diabetes, neurodegenerative diseases and cancer. Nutrient-deprivation autophagy factor 1 (NAF-1; also known as CISD2) belongs to a newly discovered class of Fe-sulfur proteins that are localized to the outer mitochondrial membrane and the endoplasmic reticulum. It has been implicated in regulating homeostasis of Fe ions, as well as the activation of autophagy through interaction with BCL-2. Here we show that small hairpin (sh)RNA-mediated suppression of NAF-1 results in the activation of apoptosis in epithelial breast cancer cells and xenograft tumors. Suppression of NAF-1 resulted in increased uptake of Fe ions into cells, a metabolic shift that rendered cells more susceptible to a glycolysis inhibitor, and the activation of cellular stress pathways that are associated with HIF1α. Our studies suggest that NAF-1 is a major player in the metabolic regulation of breast cancer cells through its effects on cellular Fe ion distribution, mitochondrial metabolism and the induction of apoptosis.
authors.affiliation: Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Holt
authors.affiliation: The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel.
authors.forename: Merav
authors.initials: M
authors.lastname: Darash-Yahana
authors.affiliation: The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel.
authors.forename: Yang Sung
authors.initials: YS
authors.lastname: Sohn
authors.affiliation: Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA.
authors.forename: Luhua
authors.initials: L
authors.lastname: Song
authors.affiliation: The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel.
authors.forename: Ola
authors.initials: O
authors.lastname: Karmi
authors.affiliation: The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel.
authors.forename: Sagi
authors.initials: S
authors.lastname: Tamir
authors.affiliation: The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel.
authors.forename: Dorit
authors.initials: D
authors.lastname: Michaeli
authors.affiliation: Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Chemistry & Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Paddock
authors.affiliation: Department of Chemistry & Biochemistry, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Jennings
authors.affiliation: Center for Theoretical Biological Physics and Department of Physics, 239 Brockman Hall, 6100 Main Street-MS-61, Rice University, Houston, TX 77005, USA.
authors.forename: José N
authors.initials: JN
authors.lastname: Onuchic
authors.affiliation: Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA Department of Mathematics, University of North Texas, Denton, TX 76203, USA.
authors.forename: Rajeev K
authors.initials: RK
authors.lastname: Azad
authors.affiliation: Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Pikarsky
authors.affiliation: The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel.
authors.forename: Ioav Z
authors.initials: IZ
authors.lastname: Cabantchik
authors.affiliation: The Alexander Silberman Institute of Life Science, Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram, Jerusalem 91904, Israel rachel@mail.huji.ac.il ronmittler@gmail.com.
authors.forename: Rachel
authors.initials: R
authors.lastname: Nechushtai
authors.affiliation: Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA rachel@mail.huji.ac.il ronmittler@gmail.com.
authors.forename: Ron
authors.initials: R
authors.lastname: Mittler
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D053148:Caspase 3 / Q000378:metabolism; D002452:Cell Count; D045744:Cell Line, Tumor; D002470:Cell Survival; D004734:Energy Metabolism; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D005260:Female; D006019:Glycolysis; D006657:Histones / Q000378:metabolism; D006801:Humans; D007477:Ions; D007501:Iron / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D017382:Reactive Oxygen Species / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D013312:Stress, Physiological; D023041:Xenograft Model Antitumor Assays
chemical_list: C523851:CISD2 protein, human; C468783:H2AX protein, human; D006657:Histones; D007477:Ions; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; D007501:Iron; D053148:Caspase 3
keywords: Apoptosis; Cancer; Mitochondria; NAF-1; NEET proteins; ROS