Hypoxia, glucose metabolism and the Warburg's effect.
As described by Warburg more than 50 years ago, tumour cells maintain a high glycolytic rate even in conditions of adequate oxygen supply. However, most of tumours are subjected to hypoxic conditions due to the abnormal vasculature that supply them with oxygen and nutrients. Thus, glycolysis is essential for tumour survival and spread. A key step in controlling glycolytic rate is the conversion of fructose-6-P to fructose-1,6-P(2) by 6-phosphofructo-1-kinase (PFK-1). The activity of PFK-1 is allosterically controlled by fructose-2,6-P(2), the product of the enzymatic activity of a dual kinase/phosphatase family of enzymes (PFKFB1-4) that are increased in a significant number of tumour types. In turn, these enzymes are induced by hypoxia through the activation of the HIF-1 complex (hypoxia-inducible complex-1), a transcriptional activator that controls the expression of most of hypoxia-regulated genes. HIF-1 complex is overexpressed in a variety of tumours and its expression appears to correlate with poor prognosis and responses to chemo or radiotherapy. Thus, targeting PFKFB enzymes, either directly or through inhibition of HIF-1, appears as a promising approach for the treatment of certain tumours.
Unitat Bioquímica i Biologia Molecular, Departament de Ciències Fisiològiques, Campus de Ciències de la Salut, IDIBELL--Universitat de Barcelona, Barcelona, Spain. rbartrons@ub.edu
Ramon
R
Bartrons
Jaime
J
Caro
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D009857:Oncogenes / Q000502:physiology; D010085:Oxidative Phosphorylation; D025481:Phosphofructokinase-2 / Q000378:metabolism
D051793:Hypoxia-Inducible Factor 1; C506672:PFKFB4 protein, human; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2; D005947:Glucose