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Published on: January 3, 2013
Butein suppresses PD-L1 expression via downregulating STAT1 in non-small cell lung cancer
Lin Zhao1, Wenxin Zhang1, Fengming Luan2
1Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Abstract:
PD-L1 (programmed cell death ligand 1) is frequently up-regulated in tumors and is critical in tumor immune escape. In addition to antibodies that block the interaction between PD-L1 and PD-1 (programmed cell death protein 1), small-molecule compounds that suppress PD-L1 expression also exhibit significant anti-tumor effects, emerging as a new strategy targeting PD-L1. By using a cell-based screening model, we found that butein, a natural chalcone compound, significantly reduced the cytoplasm and cell surface expression of PD-L1. This effect was further validated in various non-small cell lung cancer (NSCLC) cell lines and primary cells derived from clinical NSCLC tissues. Butein inhibited PD-L1 transcription, but not the half-life of PD-L1 protein. Butein reduced STAT1 level and butein-induced PD-L1 suppression was eliminated by the absence of STAT1. By co-culture system, butein improved tumor elimination by increasing the killing ability of CD8+ T cells. By in vivo study, we further confirmed that butein downregulated PD-L1 expression and improved infiltration of CD8+ T cells in tumor tissues. Taken together, our study suggested that butein could suppress the transcription of PD-L1 via downregulating STAT1, providing a theoretical basis for the application of butein in anti-tumor therapy.
Insights
Butein, a natural compound, suppresses tumor immune escape by reducing programmed cell death ligand 1 (PD-L1) expression. This natural compound offers a new strategy for anti-tumor therapy by targeting PD-L1 via STAT1 signaling.
Area of Science:
- Oncology
- Immunology
- Natural Products Chemistry
Background:
- Programmed cell death ligand 1 (PD-L1) is upregulated in tumors, aiding immune escape.
- Targeting PD-L1 with antibodies or small molecules is a promising anti-tumor strategy.
- Natural compounds offer potential therapeutic avenues for cancer treatment.
Purpose of the Study:
- To investigate the effect of butein, a natural chalcone, on PD-L1 expression.
- To elucidate the mechanism by which butein affects PD-L1.
- To evaluate the therapeutic potential of butein in non-small cell lung cancer (NSCLC).
Main Methods:
- Cell-based screening identified butein's effect on PD-L1.
- Butein's impact on PD-L1 transcription and protein stability was assessed.
- STAT1 levels and the role of STAT1 in butein's effect were investigated.
- Co-culture and in vivo studies evaluated butein's anti-tumor activity.
Main Results:
- Butein significantly reduced PD-L1 expression in NSCLC cell lines and primary cells.
- Butein inhibited PD-L1 transcription, not protein half-life, by downregulating STAT1.
- Butein enhanced CD8+ T cell-mediated tumor elimination in vitro and in vivo.
- Tumor tissues showed reduced PD-L1 and increased CD8+ T cell infiltration after butein treatment.
Conclusions:
- Butein suppresses PD-L1 transcription through STAT1 downregulation.
- Butein enhances anti-tumor immunity by increasing CD8+ T cell activity.
- Butein demonstrates potential as a therapeutic agent for anti-PD-L1 cancer therapy.
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