Research Papers:

Fructose-2,6-Bisphosphate synthesis by 6-Phosphofructo-2-Kinase/Fructose-2,6-Bisphosphatase 4 (PFKFB4) is required for the glycolytic response to hypoxia and tumor growth

Jason Chesney, Jennifer Clark, Alden C. Klarer, Yoannis Imbert-Fernandez, Andrew N. Lane and Sucheta Telang _

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Oncotarget. 2014; 5:6670-6686. https://doi.org/10.18632/oncotarget.2213

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Jason Chesney1,*, Jennifer Clark1,*, Alden C. Klarer1, Yoannis Imbert-Fernandez1, Andrew N. Lane2 and Sucheta Telang1

1 James Graham Brown Cancer Center, Departments of Medicine (Hematology/Oncology), Pediatrics and Biochemistry and Molecular Biology, University of Louisville, Louisville, KY

2 Current address: Markey Cancer Center, University of Kentucky, Lexington, KY

* These authors contributed equally to this work


Sucheta Telang, email:

Keywords: Glycolysis, 6-Phosphofructo-2-Kinase, Fructose-2,6-Bisphosphatase, Prostate Cancer, Lung Cancer

Received: July 03, 2014 Accepted: July 11, 2014 Published: July 13, 2014


Fructose-2,6-bisphosphate (F2,6BP) is a shunt product of glycolysis that allosterically activates 6-phosphofructo-1-kinase (PFK-1) resulting in increased glucose uptake and glycolytic flux to lactate. The F2,6BP concentration is dictated by four bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) with distinct kinase:phosphatase activities. PFKFB4 is over-expressed in human cancers, induced by hypoxia and required for survival and growth of several cancer cell lines. Although PFKFB4 appears to be a rational target for anti-neoplastic drug development, it is not clear whether its kinase or phosphatase activity is required for cancer cell survival. In this study, we demonstrate that recombinant human PFKFB4 kinase activity is 4.3-fold greater than its phosphatase activity, siRNA and genomic deletion of PFKFB4 decrease F2,6BP, PFKFB4 over-expression increases F2,6BP and selective PFKFB4 inhibition in vivo markedly reduces F2,6BP, glucose uptake and ATP. Last, we find that PFKFB4 is required for cancer cell survival during the metabolic response to hypoxia, presumably to enable glycolytic production of ATP when the electron transport chain is not fully operational. Taken together, our data indicate that the PFKFB4 expressed in multiple transformed cells and tumors functions to synthesize F2,6BP. We predict that pharmacological disruption of the PFKFB4 kinase domain may have clinical utility for the treatment of human cancers.

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