YAP Expression Confers Therapeutic Vulnerability to Cuproptosis in Breast Cancer Cells by Regulating Copper Homeostasis.

IF 9.6 2区 医学 Q1 ENGINEERING, BIOMEDICAL
Zei-Wei Liu, Cheng-Ying Chu, Yu-Ling Chen, Chu-Hung Chung, Fwu-Long Mi, Ming-Hua Ho, Wen-Jing Hsu, Ming-Yi Hsieh, Ming-Chen Chiang, Cheng-Jui Huang, Pei-Wei Shueng, Ching-Chieh Yang, Chi-Ching Lee, Cheng-Wei Lin
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Abstract

Copper metabolism plays a complex role in tumor growth and cancer progression and thus holds potential as a therapeutic target. However, reliable diagnostic markers and therapeutic tools for successfully predicting personalized treatment outcomes with copper inhibition remain elusive. In this study, it is discovered that Yes-associated protein (YAP) expression conferred susceptibility toward cuproptosis. Molecular analyses revealed that YAP inhibition significantly abolished cuproptotic characteristics. Interestingly, YAP inhibition does not affect protein lipoylation but disrupts copper homeostasis. Mechanistically, YAP regulates antioxidant-1 (ATOX1), a copper chaperone, and overexpression of ATOX1 restored cuproptotic sensitivity in YAP-silenced cells. To advance copper-targeting therapy, it is identified that melatonin inhibited YAP signaling and attenuated the expression of copper metabolism-related genes. Furthermore, a copper-based functional nanomaterial, EsMP@Fu is developed, which incorporates melatonin and the cuproptosis inducer elesclomol complex with copper ions (Cu(II)) (Es:Cu). This formulation facilitates cuproptotic cytotoxicity via fucoidan-decorated nanocarrier to enhance the targeted delivery toward tumor cells. In vivo study demonstrated that EsMP@Fu significantly suppressed tumor growth by 60%, with more pronounced effects on distant metastasis and the induction of antitumor immunity. Collectively, the findings demonstrate that YAP overexpression confers sensitivity and therapeutic vulnerability to cuproptosis induction, presenting a promising strategy for precision medicine through tailored copper-based therapy.

YAP表达通过调节铜稳态赋予乳腺癌细胞治疗性铜退化易感性。
铜代谢在肿瘤生长和癌症进展中起着复杂的作用,因此具有潜在的治疗靶点。然而,可靠的诊断标记和治疗工具,成功预测个性化治疗结果铜抑制仍然难以捉摸。在这项研究中,我们发现yes相关蛋白(YAP)的表达与铜体畸形的易感性有关。分子分析表明,YAP抑制显著消除了铜原性。有趣的是,抑制YAP并不影响蛋白质脂化,但会破坏铜的体内平衡。在机制上,YAP调节抗氧化剂-1 (ATOX1),一种铜伴侣,并且在YAP沉默的细胞中,ATOX1的过表达恢复了铜的敏感性。为了推进铜靶向治疗,研究人员发现褪黑素抑制YAP信号并减弱铜代谢相关基因的表达。此外,还开发了一种铜基功能纳米材料EsMP@Fu,该材料将褪黑激素和铜还原诱导剂埃斯氯莫尔与铜离子(Cu(II)) (Es:Cu)配合物结合在一起。该配方通过岩藻胶修饰的纳米载体促进了对肿瘤细胞的铜原性细胞毒性,增强了对肿瘤细胞的靶向递送。体内研究表明,EsMP@Fu可显著抑制肿瘤生长60%,对远处转移和诱导抗肿瘤免疫的作用更为明显。总的来说,研究结果表明,YAP过表达对铜凸诱导具有敏感性和治疗脆弱性,这为精准医疗提供了一种有希望的策略,即通过量身定制的铜基治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Advanced Healthcare Materials
Advanced Healthcare Materials 工程技术-生物材料
CiteScore
14.40
自引率
3.00%
发文量
600
审稿时长
1.8 months
期刊介绍: Advanced Healthcare Materials, a distinguished member of the esteemed Advanced portfolio, has been dedicated to disseminating cutting-edge research on materials, devices, and technologies for enhancing human well-being for over ten years. As a comprehensive journal, it encompasses a wide range of disciplines such as biomaterials, biointerfaces, nanomedicine and nanotechnology, tissue engineering, and regenerative medicine.
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