Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin beta 3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery

doi:10.7150/thno.27246

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物制剂研究中心

	Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin beta 3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery
	Jin, Hongyue 1,4; He, Yang 1,4; Zhao, Pengfei 4; Hu, Ying 2; Tao, Jin 2; Chen, Jiang 3; Huang, Yongzhuo1,4
刊名	THERANOSTICS
	2019
卷号	9 期号:1 页码:265-278
关键词	Epithelial-mesenchymal transition cholesterol metabolism tumor-associated macrophages simvastatin drug resistance legumain
ISSN号	1838-7640
DOI	10.7150/thno.27246
文献子类	Article
英文摘要	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.
资助项目	973 Program, China[2014CB931900] ; NFSC[81673382] ; NFSC[81422048] ; NFSC[81521005] ; Strategic Priority Research Program of CAS[XDA12050307] ; National Special Project for Significant New Drugs Development[2018ZX09711002-010-002] ; CAS Scientific Research and Equipment Development Project[YZ201437] ; Fudan-SIMM Joint Research Fund[FU-SIMM20174009]
WOS关键词	TO-MESENCHYMAL TRANSITION ; FOCAL ADHESION KINASE ; CANCER CELLS ; LUNG-CANCER ; METASTASIS ; CONSEQUENCES ; SURVIVAL ; RAFTS
WOS研究方向	Research & Experimental Medicine
语种	英语
出版者	IVYSPRING INT PUBL
WOS记录号	WOS:000453827100006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279459]
专题	药物制剂研究中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Hu, Ying; Huang, Yongzhuo
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 2.Zhejiang Pharmaceut Coll, Ningbo 315100, Zhejiang, Peoples R China; 3.Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Jin, Hongyue,He, Yang,Zhao, Pengfei,et al. Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin beta 3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery[J]. THERANOSTICS,2019,9(1):265-278.
APA	Jin, Hongyue.,He, Yang.,Zhao, Pengfei.,Hu, Ying.,Tao, Jin.,...&Huang, Yongzhuo.(2019).Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin beta 3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery.THERANOSTICS,9(1),265-278.
MLA	Jin, Hongyue,et al."Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin beta 3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery".THERANOSTICS 9.1(2019):265-278.