Activation of apoptosis in NAF-1-deficient human epithelial breast cancer cells

Sarah H. Holt, Merav Darash-Yahana, Yang Sung Sohn, Luhua Song, Ola Karmi, Sagi Tamir, Dorit Michaeli, Yuting Luo, Mark L. Paddock, Patricia A. Jennings, José N. Onuchic, Rajeev K. Azad, Eli Pikarsky, Ioav Z. Cabantchik, Rachel Nechushtai, Ron Mittler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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 HIF1a. 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.

Original languageAmerican English
Pages (from-to)155-165
Number of pages11
JournalJournal of Cell Science
Volume129
Issue number1
DOIs
StatePublished - 2016

Bibliographical note

Publisher Copyright:
© 2016.

Keywords

  • Apoptosis
  • Cancer
  • Mitochondria
  • NAF-1
  • NEET proteins
  • ROS

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