Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin β3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery
Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin β3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery
复制标题
通过整合素 β 3/FAK 途径靶向脂质代谢以克服 EMT 相关耐药性，并使用 legumain 可激活的递送实现肿瘤相关巨噬细胞复极化
DOI：
10.7150/thno.27246
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Huang, Yongzhuo
中科院分区：
文献类型：
--
作者：
Jin, Hongyue;He, Yang;Huang, Yongzhuo
上皮间质转化（EMT）与耐药的发生密切相关。脂质代谢在EMT中起重要作用。本研究旨在探讨降脂药物辛伐他汀通过脂代谢逆转EMT相关化疗耐药的作用。方法：采用辛伐他汀联合紫杉醇治疗EMT相关耐药。基于对肿瘤细胞和肿瘤相关巨噬细胞（TAM）的双重作用，开发了肿瘤微环境激活的多功能脂质体用于药物共递送。脂质体修饰的发夹结构，可活化的细胞穿透肽，是特异性地响应于肿瘤相关蛋白酶legumain.Results：它揭示了辛伐他汀可以破坏脂筏（富含胆固醇的结构域）和抑制整合素β 3和黏着斑形成，从而抑制FAK信号通路和紫杉醇的耐药癌细胞重新敏感。此外，辛伐他汀能够重新激活肿瘤相关巨噬细胞（TAM），通过胆固醇相关LXR/ABCA 1调节促进M2至M1表型转换。复极化增加了TNF-α，但减弱了TGF-β，这反过来又重塑了肿瘤微环境并抑制了EMT。结论：本研究提供了一种以辛伐他汀为基础的纳米药物治疗策略，该策略以胆固醇代谢为靶点，逆转EMT，并抑制TAM，从而治疗耐药肿瘤。阐明抗EMT的分子途径（胆固醇/脂筏/整合素β 3/FAK和胆固醇相关的LXR/ABCA 1调节）和辛伐他汀的新应用具有临床意义。
Epithelial-mesenchymal transition (EMT) is closely associated with the development of drug resistance. Lipid metabolism plays an important role in EMT. This work was to study the cholesterol-lowering drug simvastatin for reversing EMT-associated resistance to chemotherapy via lipid metabolism.Methods: The combination of simvastatin and paclitaxel was used to overcome the EMT-associated drug resistance. For dual-action on both cancer cells and tumor-associated macrophages (TAM), the tumor microenvironment-activatable multifunctional liposomes were developed for drug codelivery. The liposomes were modified with a hairpin-structured, activatable cell-penetrating peptide that is specifically responsive to the tumor-associated protease legumain.Results: It was revealed simvastatin can disrupt lipid rafts (cholesterol-rich domains) and suppress integrin-beta 3 and focal adhesion formation, thus inhibiting FAK signaling pathway and re-sensitizing the drug-resistant cancer cells to paclitaxel. Furthermore, simvastatin was able to re-polarize tumor-associated macrophages (TAM), promoting M2-to-M1 phenotype switch via cholesterol-associated LXR/ABCA1 regulation. The repolarization increased TNF-alpha, but attenuated TGF-beta, which, in turn, remodeled the tumor microenvironment and suppressed EMT. The liposomal formulation achieved enhanced treatment efficacy.Conclusion: This study provides a promising simvastatin-based nanomedicine strategy targeting cholesterol metabolism to reverse EMT and repolarize TAM to treat drug-resistant cancer. The elucidation of the molecular pathways (cholesterol/lipid raft/integrin beta 3/FAK and cholesterol-associated LXR/ABCA1 regulation) for anti-EMT and the new application of simvastatin should be of clinical significance.