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Review

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

1
Department of Histology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland
2
Department of Pathology, Pomeranian Medical University, 71-252 Szczecin, Poland
3
Department of Genetics, Wroclaw Medical University, 50-368 Wroclaw, Poland
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Department of Biochemical Engineering, Wroclaw University of Science and Technology, 50-370 Wroclaw, Poland
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Laboratoire de physique et chimie théoriques, Université de Lorraine, F-54000 Nancy, France
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Department of Biomedical and Clinical Sciences (BKV), Division of Cell Biology, Linköping University, Region Östergötland, 581 85 Linköping, Sweden
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Department of Otorhinolaryngology in Linköping, Anesthetics, Operations and Specialty Surgery Center, Region Östergötland, 581 85 Linköping, Sweden
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Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
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Research Institute in Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
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Department of Physiotherapy, Wroclaw University School of Physical Education, 51-612 Wroclaw, Poland
*
Authors to whom correspondence should be addressed.
Academic Editors: Lingzhi Wang and Qiang Jeremy Wen
Cancers 2021, 13(4), 909; https://doi.org/10.3390/cancers13040909
Received: 7 January 2021 / Revised: 12 February 2021 / Accepted: 14 February 2021 / Published: 22 February 2021
(This article belongs to the Special Issue Targeting Cancer Metastasis)
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.
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. View Full-Text
Keywords: PFKFB3; PFKFB4; PFK-2; 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; 3PO; PFK-158; PFK-15; autophagy; angiogenesis; cancer PFKFB3; PFKFB4; PFK-2; 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; 3PO; PFK-158; PFK-15; autophagy; angiogenesis; cancer
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MDPI and ACS Style

Kotowski, K.; Rosik, J.; Machaj, F.; Supplitt, S.; Wiczew, D.; Jabłońska, K.; Wiechec, E.; Ghavami, S.; Dzięgiel, P. Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets. Cancers 2021, 13, 909. https://doi.org/10.3390/cancers13040909

AMA Style

Kotowski K, Rosik J, Machaj F, Supplitt S, Wiczew D, Jabłońska K, Wiechec E, Ghavami S, Dzięgiel P. Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets. Cancers. 2021; 13(4):909. https://doi.org/10.3390/cancers13040909

Chicago/Turabian Style

Kotowski, Krzysztof, Jakub Rosik, Filip Machaj, Stanisław Supplitt, Daniel Wiczew, Karolina Jabłońska, Emilia Wiechec, Saeid Ghavami, and Piotr Dzięgiel. 2021. "Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets" Cancers 13, no. 4: 909. https://doi.org/10.3390/cancers13040909

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