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Myoferlin targeting triggers mitophagy and primes ferroptosis in pancreatic cancer cells

Authors
  • Rademaker, Gilles
  • Boumahd, Yasmine
  • Peiffer, Raphaël
  • Anania, Sandy
  • Wissocq, Tom
  • Liégeois, Maude
  • Luis, Géraldine
  • Sounni, Nor Eddine
  • Agirman, Ferman
  • Maloujahmoum, Naïma
  • De Tullio, Pascal
  • Thiry, Marc
  • Bellahcene, Akeila
  • Castronovo, Vincenzo
  • Peulen, Olivier
Publication Date
Jul 01, 2022
Source
ORBi
Keywords
Language
English
License
Green
External links

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.

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