Kaempferol Induces DNA Damage in Colorectal Cancer Cells by Regulating the MiR-195/miR-497-PFKFB4-Mediated Nonoxidative Pentose Phosphate Pathway

Abstract

Kaempferol is a flavonoid widely found in fruits and vegetables. Our previous studies have shown that kaempferol has a good inhibitory effect on colorectal cancer in vitro and in vivo, significantly inhibiting proliferation and inducing cycle arrest and apoptosis. The pentose phosphate pathway (PPP) is a branch of glucose catabolism, that provides the raw material ribose-5-phosphate (R5P) for biosynthesis for the rapid proliferation of tumor cells and is closely related to DNA damage. DNA damage has been shown to play an important role in cell cycle arrest and apoptosis. Therefore, we speculate whether kaempferol exerts the antitumor effect by inducing DNA damage. Herein we actually found that kaempferol treatment induced DNA damage, as indicated by increased γH2AX expression and comet assay. Furthermore, kaempferol reduced R5P production by inhibiting the nonoxidative PPP, while supplementation with nucleosides rescued DNA damage. Mechanistically, kaempferol upregulates the expression of microRNA-195/497 (miR-195/497) and then suppresses PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4) expression by directly binding to its 3′-UTR, thereby inhibiting the expression of transketolase (TKT) and transaldolase (TALDO), key enzymes in the nonoxidative PPP. These data uncover new targets and pathways for the action of kaempferol and lay the foundation for its development as an adjuvant drug for the treatment of colorectal cancer.