Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells

  • Redox Biol. 2022 Jul:53:102324. doi: 10.1016/j.redox.2022.102324.
Gilles Rademaker  1 ,  Yasmine Boumahd  2 ,  Raphaël Peiffer  2 ,  Sandy Anania  2 ,  Tom Wissocq  1 ,  Maude Liégeois  3 ,  Géraldine Luis  4 ,  Nor Eddine Sounni  4 ,  Ferman Agirman  1 ,  Naïma Maloujahmoum  1 ,  Pascal De Tullio  5 ,  Marc Thiry  6 ,  Akeila Bellahcène  1 ,  Vincent Castronovo  1 ,  Olivier Peulen  7
Affiliations
  • 1. Metastasis Research Laboratory, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium.
  • 2. Metastasis Research Laboratory, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium; Center for Interdisciplinary Research on Medicines (CIRM), Mitochondria Adaptation in Cancer Group, University of Liège, B-4000, Liège, Belgium.
  • 3. Laboratory of Cellular and Molecular Immunology, GIGA Institute, University of Liège, B-4000, Liège, Belgium.
  • 4. Laboratory of Tumor and Development Biology, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium.
  • 5. Center for Interdisciplinary Research on Medicines (CIRM), Metabolomics Group, University of Liège, B-4000, Liège, Belgium.
  • 6. Laboratory of Cellular and Tissular Biology, GIGA-Neurosciences, Cell Biology L3, University of Liège, B-4000, Liège, Belgium.
  • 7. Metastasis Research Laboratory, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium; Center for Interdisciplinary Research on Medicines (CIRM), Mitochondria Adaptation in Cancer Group, University of Liège, B-4000, Liège, Belgium. Electronic address: [email protected].
PMID: 35533575 DOI: 10.1016/j.redox.2022.102324
Abstract

Myoferlin, an emerging oncoprotein, has been associated with a low survival in several Cancer types including pancreas ductal adenocarcinoma where it controls mitochondria structure and respiratory functions. Owing to the high susceptibility of KRAS-mutated Cancer cells to iron-dependent cell death, Ferroptosis, and to the high iron content in mitochondria, we investigated the relation existing between mitochondrial integrity and iron-dependent cell death. We discovered that myoferlin targeting with WJ460 pharmacological compound triggered Mitophagy and ROS accumulation culminating with lipid peroxidation and apoptosis-independent cell death. WJ460 caused a reduction of the abundance of Ferroptosis core regulators xc- cystine/glutamate transporter and GPX-4. Mitophagy inhibitor Mdivi1 and iron chelators inhibited the myoferlin-related ROS production and restored cell growth. Additionally, we reported a synergic effect between Ferroptosis inducers, erastin and RSL3, and WJ460.

Keywords
Ferroptosis; Mitochondria; Mitophagy; Myoferlin; Pancreas cancer.
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