Fauzi Yanuar Rahmat, Nakahata Shingo, Shimoda Kazuya, Matsuura Tadashi, Hagiwara Shinji, Inoue Kentaro, Moritake Hiroshi, Morishita Kazuhiro
Division of Pediatrics, Department of Developmental and Urological-Reproductive Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; Department of Biochemistry and Biomolecular, Faculty of Medicine, Brawijaya University, Malang, Indonesia.
Division of HTLV-1/ATL Carcinogenesis and Therapeutics, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, Japan.
Biochem Biophys Res Commun. 2025 Apr 5;756:151564. doi: 10.1016/j.bbrc.2025.151564. Epub 2025 Feb 28.
Previously, we developed a complete human IgG TFR1 antibody (JST-TFR09/PPMX-T003) that showed a potentially practical therapeutic effect against adult T-cell leukemia/lymphoma (ATLL) in vitro and in vivo. In the present study, to elucidate the molecular mechanism underlying ATLL cell death induced by anti-TFR1 antibodies, we performed comprehensive gene expression analysis and mass spectrometry on ATLL cells treated with PPMX-T003 antibody. These results suggest that PPMX-T003 antibody treatment of ATLL cell lines induces ferroptosis mediated by ferritin degradation. PPMX-T003 antibody-treated ATLL cell lines showed a decrease in ferritin proteins, an increase in ferrous iron (Fe), reactive oxygen species (ROS) generation, and malondialdehyde as induction of lipid peroxidation. Moreover, treatment with a ferroptosis inhibitor (ferroportin-1) inhibited the cell death induced by PPMX-T003 antibody in ATLL cells. Furthermore, NCO4A and LC3-II were induced following antibody treatment, and ferritin degradation was inhibited by lysosomal inhibitors, suggesting that ferritin degradation depends on autolysosomal system activation. Here, we introduce ferroptosis as one of the potential mechanisms of PPMX-T003 antibody, which is promising for future therapeutic antibodies targeting a wide range of leukemia and cancers, including ATLL.
此前，我们研发了一种完整的人IgG TFR1抗体（JST-TFR09/PPMX-T003），该抗体在体外和体内对成人T细胞白血病/淋巴瘤（ATLL）显示出潜在的实际治疗效果。在本研究中，为了阐明抗TFR1抗体诱导ATLL细胞死亡的分子机制，我们对用PPMX-T003抗体处理的ATLL细胞进行了全面的基因表达分析和质谱分析。这些结果表明，用PPMX-T003抗体处理ATLL细胞系可诱导由铁蛋白降解介导的铁死亡。用PPMX-T003抗体处理的ATLL细胞系显示铁蛋白水平降低、亚铁离子（Fe）增加、活性氧（ROS）生成增加以及丙二醛增加，提示脂质过氧化。此外，用铁死亡抑制剂（铁转运蛋白-1）处理可抑制PPMX-T003抗体诱导的ATLL细胞死亡。此外，抗体处理后NCO4A和LC3-II被诱导，溶酶体抑制剂可抑制铁蛋白降解，提示铁蛋白降解依赖于自溶酶体系统的激活。在此，我们介绍铁死亡是PPMX-T003抗体的潜在作用机制之一，这对于未来针对包括ATLL在内的多种白血病和癌症的治疗性抗体具有重要意义。
