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Unsaturated Fatty Acid Liposomes Selectively Regulate Glutathione Peroxidase 4 to Exacerbate Lipid Peroxidation as an
Huan Huang1, Yuling Chen1, Na Yin1
1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Abstract:
Regulating non-apoptotic cell death of cancer cells provides a promising strategy to overcome apoptosis resistance during cancer treatment. Lipids are essential components to exacerbate several non-apoptotic cell death pathways. In the present study, unsaturated fatty acid (UFA) liposomes prepared with linoleic acid, oleic acid, or α-linolenic acid have the potential to affect lipid metabolism. Notably, UFA liposomes markedly increased cellular reactive oxygen species (ROS) and down-regulated the expression of glutathione peroxidase 4 (GPX4) in tumor cells, resulting in lipid peroxidation, which in turn caused rapid membrane rupture and induced non-apoptotic cell death of tumor cells. Concomitantly, UFA liposomes induced ROS-mediated tumor-associated macrophages toward a tumoricidal phenotype to reverse the immunosuppressive tumor microenvironment. Consequently, UFA liposomes substantially inhibited tumor growth in a melanoma model by promoting lipid peroxidation, inducing non-apoptotic cell death of tumor cells, and increasing infiltration of anti-tumor immune cells at tumor sites. Therefore, UFA liposomes regulate GXP4 to exacerbate lipid peroxidation and provide a versatile liposome platform for enhancing anti-tumor therapy which could be readily extended to the delivery of anticancer agents.
Insights
Unsaturated fatty acid liposomes induce cancer cell death by promoting lipid peroxidation and reversing the tumor microenvironment. This approach enhances anti-tumor immunity and inhibits tumor growth, offering a versatile platform for cancer therapy.
Area of Science:
- Biochemistry
- Immunology
- Nanotechnology
Background:
- Apoptosis resistance is a major challenge in cancer treatment.
- Non-apoptotic cell death pathways offer alternative strategies.
- Lipids play a crucial role in various non-apoptotic cell death mechanisms.
Purpose of the Study:
- To investigate the potential of unsaturated fatty acid (UFA) liposomes in inducing non-apoptotic cancer cell death.
- To explore the effects of UFA liposomes on lipid metabolism, reactive oxygen species (ROS), and immune cells within the tumor microenvironment.
- To evaluate the therapeutic efficacy of UFA liposomes in a melanoma model.
Main Methods:
- Preparation of UFA liposomes using linoleic acid, oleic acid, or α-linolenic acid.
- Assessment of cellular ROS levels and glutathione peroxidase 4 (GPX4) expression in tumor cells.
- Analysis of lipid peroxidation, membrane integrity, and cell death pathways.
- Evaluation of tumor-associated macrophage (TAM) phenotype and anti-tumor immune cell infiltration.
- Inhibition of tumor growth in a melanoma mouse model.
Main Results:
- UFA liposomes significantly increased cellular ROS and decreased GPX4 expression in tumor cells.
- This led to enhanced lipid peroxidation, membrane rupture, and non-apoptotic cell death.
- UFA liposomes modulated TAMs towards a tumoricidal phenotype, reversing immunosuppression.
- Substantial inhibition of tumor growth was observed, accompanied by increased anti-tumor immune cell infiltration.
Conclusions:
- UFA liposomes effectively induce non-apoptotic cancer cell death by regulating GPX4 and promoting lipid peroxidation.
- UFA liposomes reprogram the tumor microenvironment by activating anti-tumor immunity.
- UFA liposomes represent a promising platform for enhancing anti-cancer therapy and drug delivery.
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