Targeting Glycolytic Metabolism in Cancer

Abstract

Tumors exhibit high glucose uptake and glycolysis even in the presence of oxygen (i.e. the Warburg effect) and this metabolic phenotype serves to satisfy their increased requirement for energy and biosynthetic intermediates. Tumor glucose metabolism is stimulated in part by fructose‐2,6‐bisphosphate (F26BP), which is the product of a family of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatases (PFKFB1–4) and activates a key rate‐limiting enzyme in glycolysis, 6‐phosphofructo‐1‐kinase (PFK‐1). We have found that the PFKFB4 family member is over‐expressed in human tumors and highly induced by HIF‐1α and that silencing PFKFB4 expression markedly reduced F26BP, glucose metabolism, cell survival and the growth of xenograft tumors in vivo. Using virtual screening, we recently discovered a novel small molecule inhibitor of PFKFB4, 5MPN, that selectively inhibits recombinant PFKFB4 activity, and decreases glucose metabolism, proliferation and tumor growth and have now identified a 5MPN derivative that is significantly more effective at decreasing glucose metabolism and proliferation in cancer cells and markedly reduces the growth of established tumors in vivo, without systemic toxicity. Since our previous studies have determined the PFKFB3 family member to be a dominant source of F26BP in cancer cells and additionally have demonstrated co‐expression of the PFKFB4 and PFKFB3 enzymes in multiple patient‐derived cancers, we compared the effects of silencing PFKFB4 and PFKFB3 in human cancer cell lines in vitro. We unexpectedly found that PFKFB4 expression is increased by PFKFB3 silencing, suggesting that PFKFB4 may compensate for decreased PFKFB3 expression and activity. Importantly, an inhibitor of PFKFB3 (PFK158) is currently in Phase I trials and compensation by PFKFB4 may limit the clinical efficacy of this and other PFKFB3 inhibitors. We then examined the effects of simultaneous silencing of PFKFB4 and PFKFB3 on cancer cell lines and observed that co‐knockdown led to a significant decrease in cell viability and glycolysis and a near‐complete abrogation of anchorage independent growth in vitro and, additionally, found that simultaneous small molecule inhibition of the PFKFB4 and PFKFB3 enzymes in vitro resulted in a synergistic decrease in cell viability. Taken together, our data indicate that targeting PFKFB4 may be a valid therapeutic option against cancer and strongly support the further development of PFKFB4 small molecule inhibitors as well as the co‐targeting of PFKFB4 and PFKFB3 as potential strategies for the treatment of cancer.Support or Funding InformationNIH REACH Program Kentucky Lung Cancer Research ProgramThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.