Wu Xiangping, Wu Qingnan, Wang Yan, Liu Yehai, Li Zhenhao, Liu Qingchuan, Huang Zhengming, Li Mingyan, Zhang Bin, Zhan Qimin
Department of Otolaryngology-Head & Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
Chin J Cancer Res. 2023 Apr 30;35(2):176-190. doi: 10.21147/j.issn.1000-9604.2023.02.07.
Ferroptosis is a novel cell death process which displays a promising role in cancer treatment. However, clinically available drugs targeting ferroptosis are rarely used, and yet there are no studies reporting on inducing ferroptosis via Chinese herbal extracts. Here we explored the tumor inhibition effects of () on oral squamous cell carcinoma (OSCC). Specifically, we aimed to clarify the biological mechanism of components in the dietary, aqueous-soluble sporoderm-removed spore powder (A-GSP).
Preliminary transcriptome analysis revealed the significant enrichment of the ferroptosis pathway. Cellular Fe, glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS) and lipid peroxide levels were measured to identify ferroptosis occurrence. Western blotting was used to measure ferroptosis-related proteins. Changes in mitochondria morphology and function were observed with transmission electron microscopy (TEM) and ATP detection assays. Ferroptosis inhibitor ferrostatin-1 was then used to verify the anti-tumor effects of A-GSP. Finally, nude mice xenograft models of oral cancer confirmed that A-GSP inhibited tumor growth.
A-GSP promoted ferroptosis in oral cancer cells by inducing Fe influx, GSH depletion, as well as lipid peroxide and ROS accumulation. Ferroptosis-related proteins exhibited corresponding changes, particularly Acyl-coA synthetase long chain family member 4 (ACSL4) increase and glutathione peroxidase 4 (GPX4) decrease. A-GSP considerably lowered mitochondrial volume and ridge number, while significantly decreasing ATP production. Ferrostatin-1 reversed all of these A-GSP-induced changes. , A-GSP exerted a ferroptosis-mediated tumor-suppressing effect without observable adverse reactions.
Our findings demonstrate the therapeutic potential of A-GSP for treating patients with OSCC by targeting ferroptosis.
铁死亡是一种新型细胞死亡过程，在癌症治疗中显示出有前景的作用。然而，临床上可获得的靶向铁死亡的药物很少被使用，并且尚无关于通过中草药提取物诱导铁死亡的研究报道。在此，我们探讨了（）对口腔鳞状细胞癌（OSCC）的肿瘤抑制作用。具体而言，我们旨在阐明膳食中水溶性去孢壁孢子粉（A-GSP）成分的生物学机制。
初步转录组分析显示铁死亡途径显著富集。测量细胞内铁、谷胱甘肽（GSH）、丙二醛（MDA）、活性氧（ROS）和脂质过氧化物水平以确定铁死亡的发生。蛋白质印迹法用于检测铁死亡相关蛋白。用透射电子显微镜（TEM）和ATP检测法观察线粒体形态和功能的变化。然后使用铁死亡抑制剂铁抑素-1来验证A-GSP的抗肿瘤作用。最后，口腔癌裸鼠异种移植模型证实A-GSP抑制肿瘤生长。
A-GSP通过诱导铁流入、GSH耗竭以及脂质过氧化物和ROS积累促进口腔癌细胞的铁死亡。铁死亡相关蛋白表现出相应变化，特别是酰基辅酶A合成酶长链家族成员4（ACSL4）增加和谷胱甘肽过氧化物酶-4（GPX4）减少。A-GSP显著降低线粒体体积和嵴数量，同时显著降低ATP生成。铁抑素-1逆转了所有这些A-GSP诱导的变化。此外，A-GSP发挥了铁死亡介导的肿瘤抑制作用，且无明显不良反应。
我们的研究结果证明了A-GSP通过靶向铁死亡治疗OSCC患者的治疗潜力。
