The molecular basis of targeting PFKFB3 as a therapeutic strategy against cancer.

6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatases (PFKFBs) are bifunctional enzymes which regulate the transformation between fructose-2, 6-bisphosphate (F2, 6BP) and fructose-6-phosphate (F6P) in the process of glucose metabolism. Among the four isozymes (PFKFB1-4), PFKFB3 has stronger kinase activity than phosphatase activity, resulting in the synthesis of F2, 6BP and the promotion of glycolysis. Additionally, PFKFB3 plays a key role in cell cycle regulation. It has been confirmed that PFKFB3 is upregulated in a variety of tumor cells, and inhibition of it results in suppression of the growth of tumor cells by downregulating the glycolytic flux. It is expected to release drug resistance and prevent disease progression by PFKFB3 inhibition. Recent studies have also shown that the efficacy of PFKFB3 inhibition in tumor cells is not only related to glycolysis, but also autophagy. Here, we have reviewed the biological characteristics of PFKFB3, the regulation pathway of glucose metabolism manipulated by PFKFB3, and other regulatory mechanisms in hematologic and non-hematologic malignant tumor cells.