Carbon source metabolism and its regulation in cancer cells

Abstract

Cancer cell proliferation and progression require sufficient supplies of nutrients including carbon sources, nitrogen sources, and molecular oxygen. Particularly, carbon sources and molecular oxygen are critical for the generation of ATP and building blocks, and for the maintenance of intracellular redox status. However, solid tumors frequently outgrow the blood supply, resulting in nutrient insufficiency. Accordingly, cancer cell metabolism shows aberrant biochemical features that are consequences of oncogenic signaling and adaptation. Those adaptive metabolism features, including the Warburg effect and addiction to glutamine, may form the biochemical basis for resistance to chemotherapy and radiation. A better understanding of the regulatory mechanisms that link the signaling pathways to adaptive metabolic reprogramming may identify novel biomarkers for drug development. In this review, we focus on the regulation of carbon source utilization at a cellular level, emphasizing its relevance to proliferative biosynthesis in cancer cells. We summarize the essential needs of proliferating cells and the metabolic features of glucose, lipids, and glutamine, and we review the roles of transcription regulators (i.e., HIF-1, c-Myc, and p53) and two major oncogenic signaling pathways (i.e., PI3K-Akt and MAPK) in regulating the utilization of carbon sources. Finally, the effects of glucose on cell proliferation and perspective from both biochemical and cellular angles are discussed.

FIGURE 1

Summary of the major types of carbon sources for cancer cells. A. Glucose is a universal carbon source that may fulfill all cell needs for carbon. Glucose-6 phosphate (G6P), derived from glucose, is the common substrate for multiple metabolic pathways. Specifically, the pentose phosphate pathway (PPP) regulated by G6PD activity is responsible for the production of NADPH, riboses, and other metabolites for biosynthesis. Glycolysis, regulated by PFK1 activity, generates pyruvate, which may be either oxidized to acetyl-CoA, or reduced to lactate. Pyruvate, acetyl CoA, and other metabolites of the glycolytic pathway can be used for biosynthesis. B. The function of fatty acids as a carbon source is limited to the generation of acetyl CoA, which can be used either for oxygen-dependent, electron transfer chain-dependent generation of ATP, or for some biosynthetic pathways. Note that fatty acids can be directly used for the biosynthesis of phospholipids. C. Glutamine (Gln) serves as a precursor of glutamate; both glutamate and glutamine have important roles in nitrogen-required anabolic pathways, including the synthesis of nucleotides, proteins, glutathione, heme, polyamines, and non-essential amino acids. Importantly, through transamination or oxidative deamination, glutamate can be converted to α-ketoglutarate (α-KG), which links amino acid metabolism to carbon source metabolism. By entering the Krebs cycle, α-KG can be either directly oxidized as an energy source or used in anaplerotic reactions and converted to other metabolites such as malate and isocitrate, which can be used to generate NADPH. In some types of cells, α-KG can be converted to G6P through gluconeo-genesis. If the conversion of Gln to glucose is sufficiently efficient, theoretically Gin should be able to replace glucose as a universal carbon source.

FIGURE 2

Oncogenic signaling promotes cancer cell progression through transcriptional reprogramming and metabolic reprogramming. Based on our current understanding, oncogenic signaling pathways either directly alter the cancer cells’ metabolism or indirectly modulate the enzyme expression levels through transcriptional reprogramming. Eventually, carbon sources and molecular oxygen are utilized to generate ATP, reducing power and a variety of carbon metabolites, which together support the active biosynthesis of biomass. Note that a nitrogen source, in the form of amino acids, also is required for biosynthesis of nitrogenous molecules, and its availability may limit the general cell growth and utilization of carbon sources.