6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 3 和 4：精细调节人类癌症中葡萄糖代谢的一对阀门。
6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 and 4: A pair of valves for fine-tuning of glucose metabolism in human cancer.
机构信息
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.
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.
出版信息
Mol Metab. 2019 Feb;20:1-13. doi: 10.1016/j.molmet.2018.11.013. Epub 2018 Dec 5.
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.
背景
癌细胞倾向于使用效率较低的糖酵解途径，而不是利用线粒体氧化磷酸化来代谢葡萄糖，即使在富含氧气的条件下也是如此，这种独特的代谢改变被称为沃伯格效应或有氧糖酵解。在成人细胞中，多功能 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶（PFKFB）家族成员负责控制果糖-2,6-二磷酸的细胞质稳态水平，果糖-2,6-二磷酸通过别构激活 6-磷酸果糖-1-激酶，该酶是糖酵解限速反应的关键酶。PFKFB3 和 PFKFB4 是在各种人类癌症中过度表达的两种主要同工酶。
综述范围
在这篇综述中，我们总结了 PFKFB3 和 PFKFB4 在癌症进展中的糖酵解和糖酵解外作用的最新发现，并讨论了针对 PFKFB3 和 PFKFB4 的潜在治疗方法。
主要结论
PFKFB3 具有最高的激酶活性，可将葡萄糖分流至糖酵解途径，而 PFKFB4 具有更高的 FBPase-2 活性，将葡萄糖重新导向戊糖磷酸途径，为脂质生物合成提供还原力并清除活性氧。PFKFB3 和 PFKFB4 的共表达为癌细胞提供了足够的葡萄糖代谢，以满足癌细胞的生物能量需求和氧化还原平衡需求。PFKFB3 的各种可逆翻译后修饰使癌细胞能够灵活地适应不同应激条件下的葡萄糖代谢。除了在肿瘤细胞葡萄糖代谢中发挥重要作用外，PFKFB3 和 PFKFB4 还广泛参与多种生物学过程，如细胞周期调节、自噬和转录调控，而无需依赖糖酵解。
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