Metabolic alterations in cancer cells and therapeutic implications

Abstract

Cancer metabolism has emerged as an important area of research in recent years. Elucidation of the metabolic differences between cancer and normal cells and the underlying mechanisms will not only advance our understanding of fundamental cancer cell biology but also provide an important basis for the development of new therapeutic strategies and novel compounds to selectively eliminate cancer cells by targeting their unique metabolism. This article reviews several important metabolic alterations in cancer cells, with an emphasis on increased aerobic glycolysis (the Warburg effect) and glutamine addiction, and discusses the mechanisms that may contribute to such metabolic changes. In addition, metabolic alterations in cancer stem cells, mitochondrial metabolism and its influence on drug sensitivity, and potential therapeutic strategies and agents that target cancer metabolism are also discussed.

Figure 1.. Glucose and glutamine metabolism in cancer cells.

Glucose and glutamine are transported through cell membranes by their respective transporters (GLUT-1, -3 and -4 for glucose; SLC5A1 and SLC7A1 for glutamine). Glucose is metabolized in the cytosol to pyruvate, which can be either converted to lactate or transported into the mitochondria for further catabolism through the tricarboxylic acid (TCA) cycle coupled with respiration through the electron transport chain (ETC). In many cancer cells, glucose is mainly used for the glycolytic pathway, leading to a generation of lactate and important metablic intermediates such as glucose-6-phosphate for the pentose phosphate pathway (PPP) that generates NADPH and ribose for maintaining redox balance and synthesis of nucleic acids. The flow of glucose into mitochondria in the form of pyruvate is relatively low in cancer cells. Glutamine is actively metabolized in cancer cells, both in the cytosol and in the mitochondria, where it is catalyzed by glutaminase to generate glutamate, which is further converted to α-ketoglutarate for utilization through the TCA cycle. Both glycolysis and the TCA cycle provide important metabolic intermediates that serve as substrates for other pathways including the synthesis of nucleic acids, fatty acids, amino acids, and glutathione. The highly active pathways in cancer cells are indicated with bold arrows, whereas the less active metabolic flows are shown with thin arrows. Some of the important enzymes involved in cancer metabolism are indicated. HKII, hexokinase-2; PKM2, pyruvate kinase M2 isoform; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; PDK-1, pyruvate dehydrogenase kinase-1; GLS, glutaminase; IDH, isocitrate dehydrogenase.

Figure 2.. Human mitochondrial DNA (mtDNA) map and mutations in cancers related to metabolism.

The human mitochondrial genome Is a 16.5 kb double-stranded circular DNA, which contains 37 genes: 13 polypeptides that are components of the electron transport complexes (ETC), 22 tRNAs, and 2 ribosomal RNAs. Mutations at the 13 ETC-encoding genes may cause alterations of the respiratory chain activity and thus affect metabolism. Each box linked to a particular mitochondrial gene region contains a partial list of mutations that have been identified in that specific mtDNA in human cancers, with the specific cancer types indicated. The numbers represent the locations of the mutated bases (C, cytosine; G, guanine; T, thymine; A, Adenine). Note that the two adjacent genes for ATPase6 and ATPase8 are shown in a single box.