Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets

Simple Summary Recently, our understanding of PFK-2 isozymes, particularly with regards to their roles in cancer, has developed significantly. This review aims to compile the most crucial achievements in this field. Due to the prevailing number of recent studies on PFKFB3 and PFKFB4, we mainly focused on these two isozymes. Here, we comprehensively describe the discoveries and observations to date related to the genetic basis, regulation of expression, and protein structure of PFKFB3/4 and discuss the functional involvement in tumor progression, metastasis, angiogenesis, and autophagy. Furthermore, we highlight crucial studies on targeting PFKFB3 and PFKFB4 for future cancer therapy. This review offers a cutting-edge condensed outline of the significance of specific PFK-2 isozymes in malignancies and can be helpful in understanding past discoveries and planning novel research in this field. Abstract Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is fructose-2,6-bisphosphate (F-2,6-BP), the level of which is strongly associated with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase activity (PFK-2/FBPase-2, PFKFB). PFK-2/FBPase-2 is a bifunctional enzyme responsible for F-2,6-BP synthesis and degradation. Four isozymes of PFKFB (PFKFB1, PFKFB2, PFKFB3, and PFKFB4) have been identified. Alterations in the levels of all PFK-2/FBPase-2 isozymes have been reported in different diseases. However, most recent studies have focused on an increased expression of PFKFB3 and PFKFB4 in cancer tissues and their role in carcinogenesis. In this review, we summarize our current knowledge on all PFKFB genes and protein structures, and emphasize important differences between the isoenzymes, which likely affect their kinase/phosphatase activities. The main focus is on the latest reports in this field of cancer research, and in particular the impact of PFKFB3 and PFKFB4 on tumor progression, metastasis, angiogenesis, and autophagy. We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options.