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

doi:10.1016/j.redox.2022.102324

Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells

Redox Biol. 2022 Jul:53:102324. doi: 10.1016/j.redox.2022.102324. Epub 2022 May 4.

Authors

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.

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 x_c^- 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ferroptosis*
Humans
Iron / metabolism
Lipid Peroxidation
Mitophagy
Pancreas
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / metabolism
Reactive Oxygen Species / metabolism

Substances

Reactive Oxygen Species
Iron