Treatment against glucose-dependent cancers through metabolic PFKFB3 targeting of glycolytic flux

Reprogrammed metabolism and high energy demand are well-established properties of cancer cells that enable tumor growth. Glycolysis is a primary metabolic pathway that supplies this increased energy demand, leading to a high rate of glycolytic flux and a greater dependence on glucose in tumor cells. Finding safe and effective means to control glycolytic flux and curb cancer cell proliferation has gained increasing interest in recent years. A critical step in glycolysis is controlled by the enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which converts fructose 6-phosphate (F6P) to fructose 2,6-bisphosphate (F2,6BP). F2,6BP allosterically activates the rate-limiting step of glycolysis catalyzed by PFK1 enzyme. PFKFB3 is often overexpressed in many human cancers including pancreatic, colon, prostate, and breast cancer. Hence, PFKFB3 has gained increased interest as a compelling therapeutic target. In this review, we summarize and discuss the current knowledge of PFKFB3 functions, its role in cellular pathways and cancer development, its transcriptional and post-translational activity regulation, and the multiple pharmacologic inhibitors that have been used to block PFKFB3 activity in cancer cells. While much remains to be learned, PFKFB3 continues to hold great promise as an important therapeutic target either as a single agent or in combination with current interventions for breast and other cancers.