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PFKFB2 regulates glycolysis and proliferation in pancreatic cancer cells

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Abstract

Tumor cells increase glucose metabolism through glycolysis and pentose phosphate pathways to meet the bioenergetic and biosynthetic demands of rapid cell proliferation. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are key regulators of glucose metabolism via their synthesis of fructose-2,6-bisphosphate (F2,6BP), a potent activator of glycolysis. Previous studies have reported the co-expression of PFKFB isozymes, as well as the mRNA splice variants of particular PFKFB isozymes, suggesting non-redundant functions. Majority of the evidence demonstrating a requirement for PFKFB activity in increased glycolysis and oncogenic properties in tumor cells comes from studies on PFKFB3 and PFKFB4 isozymes. In this study, we show that the PFKFB2 isozyme is expressed in tumor cell lines of various origin, overexpressed and localizes to the nucleus in pancreatic adenocarcinoma, relative to normal pancreatic tissue. We then demonstrate the differential intracellular localization of two PFKFB2 mRNA splice variants and that, when ectopically expressed, cytoplasmically localized mRNA splice variant causes a greater increase in F2,6BP which coincides with an increased glucose uptake, as compared with the mRNA splice variant localizing to the nucleus. We then show that PFKFB2 expression is required for steady-state F2,6BP levels, glycolytic activity, and proliferation of pancreatic adenocarcinoma cells. In conclusion, this study may provide a rationale for detailed investigation of PFKFB2’s requirement for the glycolytic and oncogenic phenotype of pancreatic adenocarcinoma cells.

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Abbreviations

F6P:

Fructose-6-phosphate

F1,6BP:

Fructose-1,6-bisphosphate

F2,6BP:

Fructose-2,6-bisphosphate

PFK1:

6-Phosphofructo-1-kinase

NADPH:

Nicotinamide adenine dinucleotide phosphate

PFKFB:

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase

PPi-PFK:

Pyrophosphate-dependent phosphofructokinase

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Acknowledgements

This study was supported by the Scientific and Technological Research Council of Turkey (TUBITAK#114Z496). SCO was the recipient of a predoctoral training grant from TUBITAK (#2214).

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Authors and Affiliations

  1. Koc University Research Center for Translational Medicine (KUTTAM), 34010, Istanbul, Turkey

    Selahattin C. Ozcan

  2. Department of Biochemistry, School of Veterinary Medicine, Blok A, Bursa Uludag University, 16059, Bursa, Turkey

    Aybike Sarioglu, Tugba H. Altunok, Saime Guzel, Yunus Gurpinar & Abdullah Yalcin

  3. Department of Pathology, School of Veterinary Medicine, Bursa Uludag University, 16059, Bursa, Turkey

    Ahmet Akkoc

  4. Department of Histology & Embryology, School of Veterinary Medicine, Bursa Uludag University, 16059, Bursa, Turkey

    Sabire Guler

  5. J. G. Brown Cancer Center, University of Louisville, Louisville, KY, 40202, USA

    Yoannis Imbert-Fernandez, Amy L. Clem & Jason A. Chesney

  6. Department of Molecular Enzymology, Coastal Agrobiotechnology Institute, National University of the Littoral, 3000, Santa Fe, Argentina

    Robertino J. Muchut & Alberto A. Iglesias

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  1. Selahattin C. Ozcan
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Contributions

SCO and AY designed the experiments; SCO, AS, THA, SG, YG and ALC carried out cell culture, gene expression and protein analyses; SCO and AY conducted immunofluorescence analyses; AA and SG performed immunohistochemistry analyses; RJM and AAI isolated and tested PPi-PFK activity; SCO, THA and AY performed F2,6BP analyses; SCO and YIF carried out glucose uptake and glycolytic activity analyses; JAC revised the manuscript critically; AY and SCO wrote the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Abdullah Yalcin.

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Ozcan, S.C., Sarioglu, A., Altunok, T.H. et al. PFKFB2 regulates glycolysis and proliferation in pancreatic cancer cells. Mol Cell Biochem 470, 115–129 (2020). https://doi.org/10.1007/s11010-020-03751-5

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