FDX2, an iron-sulfur cluster assembly factor, is essential to prevent cellular senescence, apoptosis or ferroptosis of ovarian cancer cells

  • J Biol Chem. 2024 Sep;300(9):107678. doi: 10.1016/j.jbc.2024.107678.
Shuko Miyahara  1 ,  Mai Ohuchi  2 ,  Miyuki Nomura  2 ,  Eifumi Hashimoto  1 ,  Tomoyoshi Soga  3 ,  Rintaro Saito  3 ,  Kayoko Hayashi  2 ,  Taku Sato  2 ,  Masatoshi Saito  4 ,  Yoji Yamashita  2 ,  Muneaki Shimada  4 ,  Nobuo Yaegashi  4 ,  Hidekazu Yamada  2 ,  Nobuhiro Tanuma  5
Affiliations
  • 1. Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Japan; Department of Biochemical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan.
  • 2. Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Japan.
  • 3. Institute for Advanced Biosciences, Keio University, Tsuruoka, Japan.
  • 4. Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan.
  • 5. Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Japan; Department of Biochemical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: [email protected].
PMID: 39151727 DOI: 10.1016/j.jbc.2024.107678
Abstract

Recent studies reveal that biosynthesis of iron-sulfur clusters (Fe-Ss) is essential for cell proliferation, including that of Cancer cells. Nonetheless, it remains unclear how Fe-S biosynthesis functions in cell proliferation/survival. Here, we report that proper Fe-S biosynthesis is essential to prevent cellular senescence, Apoptosis, or Ferroptosis, depending on cell context. To assess these outcomes in Cancer, we developed an ovarian Cancer line with conditional KO of FDX2, a component of the core Fe-S assembly complex. FDX2 loss induced global downregulation of Fe-S-containing proteins and Fe2+ overload, resulting in DNA damage and p53 pathway activation, and driving the senescence program. p53 deficiency augmented DNA damage responses upon FDX2 loss, resulting in Apoptosis rather than senescence. FDX2 loss also sensitized cells to Ferroptosis, as evidenced by compromised redox homeostasis of membrane Phospholipids. Our results suggest that p53 status and phospholipid homeostatic activity are critical determinants of diverse biological outcomes of Fe-S deficiency in Cancer cells.

Keywords
DNA damage response; cancer biology; cell death; cellular senescence; gene knockout; iron metabolism; iron-sulfur protein; ovarian cancer; p53; reactive oxygen species (ROS); redox regulation; tumor metabolism.
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