Fructose 2,6-Bisphosphate in Cancer Cell Metabolism
2018
For a long time, pioneers in the field of cancer cell metabolism, such as Otto Warburg, have focused on the idea that tumor cells maintain high glycolytic rates even with adequate oxygen supply, in what is known as aerobic
glycolysisor the
Warburg effect. Recent studies have reported a more complex situation, where the tumor ecosystem plays a more critical role in cancer progression. Cancer cells display extraordinary plasticity in adapting to changes in their
tumor microenvironment, developing strategies to survive and proliferate. The proliferation of cancer cells needs a high rate of energy and metabolic substrates for biosynthesis of biomolecules. These requirements are met by the metabolic
reprogrammingof cancer cells and others present in the
tumor microenvironment, which is essential for tumor survival and spread. Metabolic
reprogramminginvolves a complex interplay between oncogenes, tumor suppressors, growth factors and local factors in the
tumor microenvironment. These factors can induce overexpression and increased activity of glycolytic isoenzymes and proteins in stromal and cancer cells which are different from those expressed in normal cells. The
fructose-6-phosphate/
fructose-1,6-bisphosphate cycle, catalyzed by 6-phosphofructo-1-kinase/
fructose 1,6-bisphosphatase(PFK1/FBPase1) isoenzymes, plays a key role in controlling glycolytic rates. PFK1/FBpase1 activities are
allosterically regulatedby
fructose-2,6-bisphosphate, the product of the enzymatic activity of the dual kinase/phosphatase family of enzymes: 6-phosphofructo-2-kinase/
fructose2,6-bisphosphatase (PFKFB1-4) and
TP53-induced glycolysisand
apoptosis regulator(TIGAR), which show increased expression in a significant number of tumor types. In this review, the functionof these isoenzymes in the regulation of metabolism, as well as the regulatory factors modulating their expression and activity in the tumor ecosystem are discussed. Targeting these isoenzymes, either directly or by inhibiting their activating factors, could be a promising approach for treating cancers.
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