Examination of Intra-Tumoral Expression of the PFKFB3 and PFKFB4 Enzymes: Implications for Targeting Glycolysis

Author(s): Lilibeth Lanceta, Renita Ranjan, Nicole Sanders, Sucheta Telang

A high rate of glycolytic activity is observed in multiple tumor types and serves to provide energy and biosynthetic precursors to support their growth and spread. The 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase family of enzymes (PFKFB1-4) have been recognized as important regulators of glycolysis due to their production of fructose-2,6-bisphosphate (F26BP) which activates a rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase (PFK-1). As a result, the expression and function of the PFKFB enzymes have been extensively evaluated. In these studies, we found that the PFKFB3 and PFKFB4 enzymes were consistently co-expressed in multiple tumor tissues. Further evaluation of their expression showed that PFKFB3 and PFKFB4 were similarly expressed in normoxia but exhibited significant expression differences under hypoxic conditions where PFKFB4 was highly induced. We additionally found that the isoforms showed different intratumoral expression wherein PFKFB4 correlated significantly with areas of hypoxia and PFKFB3 showed poor correlation. Based on their varied expression, we examined the effects of silencing both isoforms and found that co-silencing PFKFB3 and PFKFB4 significantly decreased proliferation, particularly in hypoxia. These results, although preliminary, carry implications for the potential utility of targeting both the PFKFB3 and PFKFB4 enzymes for the development of effective therapeutic approaches against cancer.