Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis.
Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis.
复制标题
DOI：
10.1016/j.redox.2023.102677
复制
发表时间：
2023-03
期刊：
影响因子：
11.4
通讯作者：
Sha Liu;Hai-liang Zhang;Jing Li;Zhixiang Ye;Tian Du;Li-Chao Li-Li-Chao-Li-2212045907;Yizhan Guo;Dong-dong Yang;Zhi-Ling Li;Jianghua Cao;Bingshuang Hu;Yu-Hong Chen;G. Feng;Zhiming Li;R. Deng;Jiajia Huang;Xiao-Feng Zhu
中科院分区：
文献类型：
--
作者：
Sha Liu;Hai-liang Zhang;Jing Li;Zhixiang Ye;Tian Du;Li-Chao Li-Li-Chao-Li-2212045907;Yizhan Guo;Dong-dong Yang;Zhi-Ling Li;Jianghua Cao;Bingshuang Hu;Yu-Hong Chen;G. Feng;Zhiming Li;R. Deng;Jiajia Huang;Xiao-Feng Zhu
铁下垂是一种铁依赖的脂质过氧化导致的程序性细胞死亡，与癌症治疗密切相关。药物铁下垂诱导剂的开发及其在癌症治疗中的合理应用是至关重要的。在这里，我们通过大规模的药物筛选，确定HDAC6抑制剂Tubasatin A是一种新型的可药物诱导的铁下垂诱导剂。通过生物素连接的Tubasatin A降压和LC/MS分析，Tubasatin A直接与Gpx4结合并抑制Gpx4的酶活性，这与其对HDAC6的抑制无关。此外，我们的结果表明，放疗不仅激活了Nrf2介导的Gpx4转录，而且还抑制了溶酶体介导的Gpx4的降解，从而诱导了癌细胞的铁下垂耐受和辐射抵抗。Tubasatin A通过抑制Gpx4酶活性来克服癌细胞的铁下垂抵抗和放射抵抗。更重要的是，Tubasatin A具有极好的生物利用度，其在小鼠异种移植模型中显著促进放射诱导的脂质过氧化和肿瘤抑制的能力证明了这一点。我们的发现确定了一种新的可药物的铁下垂诱导剂Tubasatin A，它可以增强放射介导的抗肿瘤效果。这项工作为Tubasatin A的临床评估提供了令人信服的理论基础，特别是在结合放射治疗的情况下。
Ferroptosis, an iron-dependent lipid peroxidation-driven programmed cell death, is closely related to cancer therapy. The development of druggable ferroptosis inducers and their rational application in cancer therapy are critical. Here, we identified Tubastatin A, an HDAC6 inhibitor as a novel druggable ferroptosis inducer through large-scale drug screening. Tubastatin A directly bonded to GPX4 and inhibited GPX4 enzymatic activity through biotin-linked Tubastatin A putdown and LC/MS analysis, which is independent of its inhibition of HDAC6. In addition, our results showed that radiotherapy not only activated Nrf2-mediated GPX4 transcription but also inhibited lysosome-mediated GPX4 degradation, subsequently inducing ferroptosis tolerance and radioresistance in cancer cells. Tubastatin A overcame ferroptosis resistance and radioresistance of cancer cells by inhibiting GPX4 enzymatic activity. More importantly, Tubastatin A has excellent bioavailability, as demonstrated by its ability to significantly promote radiotherapy-induced lipid peroxidation and tumour suppression in a mouse xenograft model. Our findings identify a novel druggable ferroptosis inducer, Tubastatin A, which enhances radiotherapy-mediated antitumor effects. This work provides a compelling rationale for the clinical evaluation of Tubastatin A, especially in combination with radiotherapy.