Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells
Gilles Rademaker,
Yasmine Boumahd,
Raphaël Peiffer,
Sandy Anania,
Tom Wissocq,
Maude Liégeois,
Géraldine Luis,
Nor Eddine Sounni,
Ferman Agirman,
Naïma Maloujahmoum,
Pascal De Tullio,
Marc Thiry,
Akeila Bellahcène,
Vincent Castronovo,
Olivier Peulen
Affiliations
Gilles Rademaker
Metastasis Research Laboratory, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium
Yasmine Boumahd
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
Raphaël Peiffer
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
Sandy Anania
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
Tom Wissocq
Metastasis Research Laboratory, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium
Maude Liégeois
Laboratory of Cellular and Molecular Immunology, GIGA Institute, University of Liège, B-4000, Liège, Belgium
Géraldine Luis
Laboratory of Tumor and Development Biology, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium
Nor Eddine Sounni
Laboratory of Tumor and Development Biology, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium
Ferman Agirman
Metastasis Research Laboratory, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium
Naïma Maloujahmoum
Metastasis Research Laboratory, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium
Pascal De Tullio
Center for Interdisciplinary Research on Medicines (CIRM), Metabolomics Group, University of Liège, B-4000, Liège, Belgium
Marc Thiry
Laboratory of Cellular and Tissular Biology, GIGA-Neurosciences, Cell Biology L3, University of Liège, B-4000, Liège, Belgium
Akeila Bellahcène
Metastasis Research Laboratory, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium
Vincent Castronovo
Metastasis Research Laboratory, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium
Olivier Peulen
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; Corresponding author. Metastasis Research Laboratory, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium.
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.
