6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 and 4: A pair of valves for fine-tuning of glucose metabolism in human cancer

Mei Yi; Yuanyuan Ban; Yixin Tan; Wei Xiong; Guiyuan Li; Bo Xiang

Molecular Metabolism (Feb 2019)

6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 and 4: A pair of valves for fine-tuning of glucose metabolism in human cancer

Mei Yi,
Yuanyuan Ban,
Yixin Tan,
Wei Xiong,
Guiyuan Li,
Bo Xiang

Affiliations

Mei Yi: Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, Hunan 410013, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Department of Dermatology, Xiangya Hospital, The Central South University, Changsha, 410008, Hunan, China
Yuanyuan Ban: Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, Hunan 410013, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
Yixin Tan: Department of Dermatology, Second Xiangya Hospital, The Central South University, Hunan Key Laboratory of Medical Epigenetics, Changsha, 410011, Hunan, China
Wei Xiong: Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, Hunan 410013, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
Guiyuan Li: Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, Hunan 410013, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
Bo Xiang: Hunan Provincial Cancer Hospital and Cancer Hospital Affiliated to Xiangya Medical School, The Central South University, Changsha, Hunan 410013, China; The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute and School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China; The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China; Corresponding author. Cancer Hospital Affiliated to Xiangya School of Medicine, Central South University, Tongzipo Road, Changsha, Hunan 410013, China. Fax: +86 731 84805383.

Journal volume & issue: Vol. 20
pp. 1 – 13

Abstract

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Background: Cancer cells favor the use of less efficient glycolysis rather than mitochondrial oxidative phosphorylation to metabolize glucose, even in oxygen-rich conditions, a distinct metabolic alteration named the Warburg effect or aerobic glycolysis. In adult cells, bifunctional 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB) family members are responsible for controlling the steady-state cytoplasmic levels of fructose-2,6-bisphosphate, which allosterically activates 6-phosphofructo-1-kinase, the key enzyme catalyzing the rate-limiting reaction of glycolysis. PFKFB3 and PFKFB4 are the two main isoenzymes overexpressed in various human cancers. Scope of review: In this review, we summarize recent findings on the glycolytic and extraglycolytic roles of PFKFB3 and PFKFB4 in cancer progression and discuss potential therapies for targeting of PFKFB3 and PFKFB4. Major conclusions: PFKFB3 has the highest kinase activity to shunt glucose toward glycolysis, whereas PFKFB4 has more FBPase-2 activity, redirecting glucose toward the pentose phosphate pathway, providing reducing power for lipid biosynthesis and scavenging reactive oxygen species. Co-expression of PFKFB3 and PFKFB4 provides sufficient glucose metabolism to satisfy the bioenergetics demand and redox homeostasis requirements of cancer cells. Various reversible post-translational modifications of PFKFB3 enable cancer cells to flexibly adapt glucose metabolism in response to diverse stress conditions. In addition to playing important roles in tumor cell glucose metabolism, PFKFB3 and PFKFB4 are widely involved in multiple biological processes, such as cell cycle regulation, autophagy, and transcriptional regulation in a non-glycolysis-dependent manner. Keywords: Warburg effect, Aerobic glycolysis, 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase, Pentose phosphate pathway, Metabolic reprogramming

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

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