Konishi Hiroto, Haga Yuya, Okumura Moe, Tsujino Hirofumi, Higashisaka Kazuma, Tsutsumi Yasuo
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Cell Death Discov. 2024 Mar 1;10(1):108. doi: 10.1038/s41420-024-01884-w.
Various treatment options, such as molecular targeted drugs and immune checkpoint blockades, are available for patients with cancer. However, some cancer types are refractory to molecular targeted therapies or acquire drug resistance after long-term treatment. Thus, ferroptosis, a newly defined type of programmed cell death caused by the iron-dependent accumulation of lipid peroxidation, has gained attention as a novel cancer treatment strategy. Understanding cell-cell interactions in the tumor microenvironment is important for the clinical application of ferroptosis inducers. However, the effects of cell-cell interactions on ferroptosis sensitivity remain unclear. Thus, we aimed to evaluate the effects of macrophage-cancer cell interactions on ferroptosis induction. Coculture experiments showed that conditioned medium prepared from macrophages did not alter the ferroptosis sensitivity of cancer cells. By contrast, coculture via transwell, which enables cell-cell interactions through secretion, increased the sensitivity of cancer cells to ferroptosis inducers. Additionally, direct coculture increased the susceptibility of cancer cells to RSL3-induced ferroptosis. Mechanistically, coculture with macrophages upregulated the levels of intracellular ferrous ions and lipid peroxidation in cancer cells. These findings provide novel insights into the mechanisms by which cell-cell interactions influence ferroptosis induction and application of ferroptosis inducers as a cancer treatment option.
对于癌症患者有多种治疗选择，如分子靶向药物和免疫检查点阻断剂。然而，某些癌症类型对分子靶向治疗难治，或在长期治疗后产生耐药性。因此，铁死亡作为一种新定义的由铁依赖性脂质过氧化积累引起的程序性细胞死亡类型，已作为一种新型癌症治疗策略受到关注。了解肿瘤微环境中的细胞间相互作用对于铁死亡诱导剂的临床应用很重要。然而，细胞间相互作用对铁死亡敏感性的影响仍不清楚。因此，我们旨在评估巨噬细胞与癌细胞相互作用对铁死亡诱导的影响。共培养实验表明，由巨噬细胞制备的条件培养基不会改变癌细胞的铁死亡敏感性。相比之下，通过Transwell进行的共培养，其能够通过分泌实现细胞间相互作用，增加了癌细胞对铁死亡诱导剂的敏感性。此外，直接共培养增加了癌细胞对RSL3诱导的铁死亡的易感性。从机制上讲，与巨噬细胞共培养会上调癌细胞内亚铁离子水平和脂质过氧化水平。这些发现为细胞间相互作用影响铁死亡诱导的机制以及铁死亡诱导剂作为癌症治疗选择的应用提供了新的见解。
