Theranostics 2019; 9(1):265-278. doi:10.7150/thno.27246

Research Paper

Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin β3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery

Hongyue Jin1,2, Yang He1,2, Pengfei Zhao1, Ying Hu3✉, Jin Tao3, Jiang Chen4, Yongzhuo Huang1,2✉

1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China,
2. University of Chinese Academy of Sciences, Beijing 100049, China
3. Zhejiang Pharmaceutical College, Ningbo 315100, China
4. Fudan University School of Pharmacy, Shanghai 201203, China

Abstract

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-β3 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-α, but attenuated TGF-β, 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 β3/FAK and cholesterol-associated LXR/ABCA1 regulation) for anti-EMT and the new application of simvastatin should be of clinical significance.

Keywords: Epithelial-mesenchymal transition, cholesterol metabolism, tumor-associated macrophages, simvastatin, drug resistance, legumain

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How to cite this article:
Jin H, He Y, Zhao P, Hu Y, Tao J, Chen J, Huang Y. Targeting lipid metabolism to overcome EMT-associated drug resistance via integrin β3/FAK pathway and tumor-associated macrophage repolarization using legumain-activatable delivery. Theranostics 2019; 9(1):265-278. doi:10.7150/thno.27246. Available from http://www.thno.org/v09p0265.htm