1. Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells.
- Author
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Rademaker G, Boumahd Y, Peiffer R, Anania S, Wissocq T, Liégeois M, Luis G, Sounni NE, Agirman F, Maloujahmoum N, De Tullio P, Thiry M, Bellahcène A, Castronovo V, and Peulen O
- Subjects
- Humans, Iron metabolism, Lipid Peroxidation, Mitophagy, Pancreas, Reactive Oxygen Species metabolism, Ferroptosis, Pancreatic Neoplasms genetics, Pancreatic Neoplasms metabolism
- 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., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2022
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