D-mannose suppresses the angiogenesis and progression of colorectal cancer

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 nuclear translocation of TFE3, and promotes lysosomal biogenesis, thereby increasing lysosomal-mediated degradation of VEGFR2. Thus, D-mannose significantly suppressed proliferation, migration and capillary formation of human umbilical vein endothelial cells (HUVEC) in vitro . Oral administration of D-mannose dramatically inhibited 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 clinical treatment of colorectal cancer (CRC).