Hirata Yusuke, Yamada Yuto, Taguchi Soma, Kojima Ryota, Masumoto Haruka, Kimura Shinnosuke, Niijima Takuya, Toyama Takashi, Kise Ryoji, Sato Emiko, Uchida Yasunori, Ito Junya, Nakagawa Kiyotaka, Taguchi Tomohiko, Inoue Asuka, Saito Yoshiro, Noguchi Takuya, Matsuzawa Atsushi
Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Laboratory of Molecular Biology and Metabolism, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Cell Death Dis. 2024 Dec 6;15(12):884. doi: 10.1038/s41419-024-07237-w.
Conjugated fatty acids (CFAs) have been known for their anti-tumor activity. However, the mechanism of action remains unclear. Here, we identify CFAs as inducers of glutathione peroxidase 4 (GPX4) degradation through chaperone-mediated autophagy (CMA). CFAs, such as (10E,12Z)-octadecadienoic acid and α-eleostearic acid (ESA), induced GPX4 degradation, generation of mitochondrial reactive oxygen species (ROS) and lipid peroxides, and ultimately ferroptosis in cancer cell lines, including HT1080 and A549 cells, which were suppressed by either pharmacological blockade of CMA or genetic deletion of LAMP2A, a crucial molecule for CMA. Mitochondrial ROS were sufficient and necessary for CMA-dependent GPX4 degradation. Oral administration of an ESA-rich oil attenuated xenograft tumor growth of wild-type, but not that of LAMP2A-deficient HT1080 cells, accompanied by increased lipid peroxidation, GPX4 degradation and cell death. Our study establishes mitochondria as the key target of CFAs to trigger lipid peroxidation and GPX4 degradation, providing insight into ferroptosis-based cancer therapy.
共轭脂肪酸（CFAs）因其抗肿瘤活性而闻名。然而，其作用机制仍不清楚。在此，我们确定CFAs是通过伴侣介导的自噬（CMA）诱导谷胱甘肽过氧化物酶4（GPX4）降解的物质。CFAs，如（10E，12Z）-十八碳二烯酸和α-桐酸（ESA），诱导GPX4降解、线粒体活性氧（ROS）和脂质过氧化物的产生，并最终在包括HT1080和A549细胞在内的癌细胞系中引发铁死亡，而CMA的药理学阻断或CMA关键分子LAMP2A的基因缺失均可抑制这种铁死亡。线粒体ROS对于依赖CMA的GPX4降解是充分且必要的。口服富含ESA的油可减弱野生型异种移植瘤的生长，但对LAMP2A缺陷型HT1080细胞的异种移植瘤生长无此作用，同时伴有脂质过氧化增加、GPX4降解和细胞死亡。我们的研究确定线粒体是CFAs触发脂质过氧化和GPX4降解的关键靶点，为基于铁死亡的癌症治疗提供了见解。
