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Published on: December 3, 2020
PPARδ Antagonist Inhibited CD47 Expression and Phagocytosis
Yilei Guo1,2, Bibimaryam Khan1, Juanjuan Shi2
1Department of Oncology, The Affiliated Wujin Hospital of Jiangsu University (The Wujin Clinical College of Xuzhou Medical University), Changzhou, Jiangsu, China.
Abstract:
Increasing evidence suggests that CD47 is highly expressed in multiple types of cancer, which could bind to SIRPα on macrophage, leading to inhibition of macrophage phagocytosis and promotion of tumor growth. However, the regulatory mechanism of CD47 gene expression is not completely clear. Our results indicated that colon cancer cells treated with GSK0660 drug, which is one of the PPARδ antagonists, significantly reduced CD47 gene and protein expression levels in a time and dose-dependent manner. CD47 reporter plasmid was constructed and dual-luciferase analysis was performed. The results suggest that GSK0660 treatment markedly reduced CD47 gene transcriptional activity. Moreover, co-cultured analysis showed that GSK0660 treatment increased phagocytosis. BALB/C mice implanted with CT-26 colon cancer cells were treated with GSK0660, and the results showed that GSK0660 significantly inhibited tumor growth. Moreover, the combination of CD47 monoclonal antibody with GSK0660 drug significantly inhibited tumor growth compared to GSK0660 or CD47 antibody treatment alone. These findings suggest that GSK0660 synergized with CD47 antibody to enhance antitumor immunotherapy.
Insights
GSK0660, a PPARδ antagonist, reduces CD47 expression and enhances macrophage phagocytosis, inhibiting colon cancer growth. Combining GSK0660 with CD47 antibody boosts antitumor immunotherapy efficacy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- CD47 is highly expressed in many cancers, inhibiting macrophage phagocytosis and promoting tumor growth.
- The regulatory mechanisms of CD47 gene expression remain incompletely understood.
- Targeting CD47 is a promising strategy for cancer immunotherapy.
Purpose of the Study:
- To investigate the effect of PPARδ antagonist GSK0660 on CD47 expression and function in colon cancer.
- To evaluate the therapeutic potential of GSK0660 alone and in combination with CD47 monoclonal antibody in a colon cancer model.
Main Methods:
- Colon cancer cells were treated with GSK0660, and CD47 gene and protein expression were analyzed.
- Dual-luciferase reporter assays were used to assess CD47 gene transcriptional activity.
- In vitro co-culture assays were performed to evaluate macrophage phagocytosis.
- In vivo studies involved implanting CT-26 colon cancer cells in BALB/C mice and treating them with GSK0660 and/or CD47 antibody.
Main Results:
- GSK0660 treatment significantly reduced CD47 gene and protein expression in a time- and dose-dependent manner.
- GSK0660 markedly decreased CD47 gene transcriptional activity.
- GSK0660 enhanced macrophage phagocytosis in vitro.
- GSK0660 significantly inhibited tumor growth in vivo.
- The combination of GSK0660 and CD47 antibody showed superior tumor growth inhibition compared to monotherapy.
Conclusions:
- PPARδ antagonist GSK0660 effectively downregulates CD47 expression and enhances anti-tumor immunity.
- GSK0660 demonstrates therapeutic potential as a monotherapy and synergizes with CD47 antibody for enhanced colon cancer immunotherapy.
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