2. Academic Validation
  3. Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells

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

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: olivier.peulen@uliege.be.
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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