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D-mannose suppresses the angiogenesis and progression of colorectal cancer
Yu Du1,2, Xinchao Zhang2, Yixin Xu1,2
1Nourse Centre for Pet Nutrition, Wuhu 241200, China.
Abstract:
Angiogenesis is an important factor influencing the development of solid tumors, and vascular endothelial growth factor receptor-2 (VEGFR2) is a central regulator of angiogenesis. Antibodies and inhibitors against VEGFR2 have been widely used in various malignancies. However, the regulatory mechanism of VEGFR2 has not been fully clarified. Here, we show that D-mannose can significantly inhibit angiogenesis and tumor growth by degrading VEGFR2. Specifically, D-mannose inactivates GSK3β by promoting the phosphorylation of GSK3β at Ser9, enhances the nuclear translocation of TFE3, and promotes lysosomal biogenesis, thereby increasing the lysosome-mediated degradation of VEGFR2. Thus, D-mannose significantly inhibits the proliferation, migration, and capillary formation of human umbilical vein endothelial cells (HUVECs) in vitro. Oral administration of D-mannose dramatically inhibits angiogenesis and tumor growth in mice. Our findings reveal a previously unrecognized anti-tumor mechanism of D-mannose by destabilizing VEGFR2 and provide a new strategy for the clinical treatment of colorectal cancer (CRC).
Insights
D-mannose inhibits tumor growth by degrading vascular endothelial growth factor receptor-2 (VEGFR2). This sugar molecule destabilizes VEGFR2, offering a novel anti-cancer strategy, particularly for colorectal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Angiogenesis is crucial for solid tumor development.
- Vascular endothelial growth factor receptor-2 (VEGFR2) is a key regulator of angiogenesis.
- VEGFR2 inhibitors are used in cancer therapy, but its regulatory mechanisms require further elucidation.
Purpose of the Study:
- To investigate the anti-tumor effects of D-mannose.
- To elucidate the mechanism by which D-mannose affects VEGFR2.
- To explore D-mannose as a potential therapeutic agent for colorectal cancer.
Main Methods:
- Investigated D-mannose's effect on angiogenesis and tumor growth in vitro and in vivo.
- Analyzed VEGFR2 degradation pathways.
- Examined the impact of D-mannose on GSK3β phosphorylation, TFE3 nuclear translocation, and lysosomal biogenesis.
Main Results:
- D-mannose significantly inhibits angiogenesis and tumor growth.
- D-mannose promotes VEGFR2 degradation via lysosomal pathways.
- D-mannose inactivates GSK3β, enhances TFE3 nuclear translocation, and increases lysosomal biogenesis.
- D-mannose reduces proliferation, migration, and capillary formation of HUVECs in vitro.
- Oral D-mannose administration inhibits tumor growth in mice.
Conclusions:
- D-mannose exerts anti-tumor effects by destabilizing VEGFR2.
- D-mannose represents a novel therapeutic strategy targeting angiogenesis.
- This study provides a new approach for colorectal cancer treatment.
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