Cancer cell metabolism: implications for therapeutic targets

Abstract

Cancer cell metabolism is characterized by an enhanced uptake and utilization of glucose, a phenomenon known as the Warburg effect. The persistent activation of aerobic glycolysis in cancer cells can be linked to activation of oncogenes or loss of tumor suppressors, thereby fundamentally advancing cancer progression. In this respect, inhibition of glycolytic capacity may contribute to an anticancer effect on malignant cells. Understanding the mechanisms of aerobic glycolysis may present a new basis for cancer treatment. Accordingly, interrupting lactate fermentation and/or other cancer-promoting metabolic sites may provide a promising strategy to halt tumor development. In this review, we will discuss dysregulated and reprogrammed cancer metabolism followed by clinical relevance of the metabolic enzymes, such as hexokinase, phosphofructokinase, pyruvate kinase M2, lactate dehydrogenase, pyruvate dehydrogenase kinase and glutaminase. The proper intervention of these metabolic sites may provide a therapeutic advantage that can help overcome resistance to chemotherapy or radiotherapy.

Figure 1

Metabolism of cancer cells is regulated by signaling pathways related to oncogenes and tumor-suppressor genes. PI3K activates AKT, which stimulates glucose uptake and flux by directly controlling glycolytic enzymes and by activating mTOR. mTOR indirectly causes metabolic changes by activating HIF. HIF activates PDK, which inactivates the mitochondrial pyruvate dehydrogenase complex and thereby inhibits the entry of pyruvate into the TCA cycle. p53 suppresses glycolysis by increasing the expression of TIGAR, supporting the expression of PTEN, and promoting oxidative phosphorylation via SCO2. Myc enhances the glycolytic pathway by increasing transcription of glycolytic enzymes and is also involved in glutamine metabolism.

Figure 2

The regulation of glucose metabolism in cancer cells. When glucose enters the cell through a glucose transporter, it is phosphorylated by HK to glucose-6-phosphate, which is further metabolized by glycolysis to pyruvate in the cytosol. Under aerobic conditions, normal cells use pyruvate dehydrogenase (PDH) to convert most pyruvate to acetyl-CoA. The acetyl-CoA is then oxidized via the TCA cycle, providing sources of ATP synthesis. In contrast, the metabolic pathways of glucose utilization in cancer are changed from ATP generation by oxidative phosphorylation to ATP generation through glycolysis. Also, for cell proliferation to occur, cancer cells require the synthesis of new macromolecules (for example, nucleic acids, lipids, proteins). Key enzymes that may be promising targets for cancer therapy are highlighted in red. TCA enzymes that are known to be mutated in cancer are shown in purple: IDH2, SDH, and FH.