Metastasis Research Laboratory, GIGA-cancer, University of Liège, Pathology Institute B23, B-4000, Liège, Belgium.
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.
Redox Biol. 2022 Jul;53:102324. doi: 10.1016/j.redox.2022.102324. Epub 2022 May 4.
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 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.
肌联蛋白是一种新兴的癌蛋白，与包括胰腺导管腺癌在内的几种癌症类型的低存活率相关，它控制着线粒体的结构和呼吸功能。由于 KRAS 突变的癌细胞对铁依赖性细胞死亡、铁死亡以及线粒体中铁含量非常敏感，我们研究了线粒体完整性与铁依赖性细胞死亡之间的关系。我们发现，用 WJ460 药理学化合物靶向肌联蛋白会触发线粒体自噬和 ROS 积累，最终导致脂质过氧化和凋亡不依赖的细胞死亡。WJ460 降低了铁死亡核心调控因子胱氨酸/谷氨酸转运体和 GPX-4 的丰度。线粒体自噬抑制剂 Mdivi1 和铁螯合剂抑制了肌联蛋白相关的 ROS 产生，并恢复了细胞生长。此外，我们还报道了铁死亡诱导剂 erastin 和 RSL3 与 WJ460 之间的协同作用。
