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

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.

• Authors: Hongyue Jin, Yang He, Pengfei Zhao, Ying Hu, Jin Tao, Jiang Chen, Yongzhuo Huang
• Journal: Theranostics (Theranostics) Vol. 9 Issue 1 Pg. 265-278 ( 2019) ISSN: 1838-7640 [Electronic] Australia
• PMID: 30662566 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Integrin beta3
• Liposomes
• Simvastatin
• Cysteine Endopeptidases
• asparaginylendopeptidase
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents (administration & dosage, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cysteine Endopeptidases (metabolism)
• Drug Carriers (metabolism)
• Drug Resistance, Neoplasm (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Focal Adhesions (drug effects)
• Heterografts
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (administration & dosage, metabolism)
• Integrin beta3 (metabolism)
• Lipid Metabolism (drug effects)
• Liposomes (metabolism)
• Macrophages (immunology)
• Male
• Mice, Inbred BALB C
• Neoplasm Transplantation
• Paclitaxel (administration & dosage, metabolism)
• Signal Transduction (drug effects)
• Simvastatin (administration & dosage, metabolism)
• Treatment Outcome