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org.clulab.demo.bio.inactive.PMC-3225393-01-Introduction-01.txt Maven / Gradle / Ivy

Cancer cells are distinguished from their normal counterparts by metabolic differences that include increased utilization of glucose by aerobic glycolysis.
This characteristic of malignant cells, known as the Warburg effect, associates a high rate of glucose consumption with enhanced lactate production in the presence of oxygen [1]. Aerobic glycolysis in cancer cells has been linked with increased expression of glycolytic genes [2], [3]. Pyruvate kinase (PK) is one of the upregulated glycolytic gene products that catalyzes the production of pyruvate and ATP from phosphoenolpyruvate (PEP) and ADP. There are four PK isoenzymes, M1, M2, L and R. The M1 isoform is expressed in most adult cells. The M2 isoform (PKM2), a splice variant of M1, is found in embryonic cells, certain normal proliferating cells and cancer cells [4]. Heterogenous nuclear ribonucleoproteins bind to PKM1 mRNA and inhibit its splicing [5]. Converting PKM2 expression to PKM1 in cancer cells reverses the Warburg effect and is associated with loss of tumorigenicity, establishing the importance of PKM2 for aerobic glycolysis and the proliferation of malignant cells [6]. The distinct region of PKM2, as compared to PKM1, functions in the allosteric activation of the enzyme by fructose-1,6-bisphosphate (FBP) [7] and its inactivation by phosphotyrosine containing proteins [8], [9]. Under these circumstances, the regulation of PKM2 activity dictates the metabolism of glucose to pyruvate, which is converted by lactate dehydrogenase (LDH) to lactate or is utilized by the mitochondrial tricarboxylic acid (TCA) cycle [10]. These findings have thus supported the need to more fully understand the signals that regulate aerobic glycolysis and PKM2 activity in malignant cells.