Fundamentals of cancer metabolism

Ralph J DeBerardinis, Navdeep S Chandel, Ralph J DeBerardinis, Navdeep S Chandel

Abstract

Tumors reprogram pathways of nutrient acquisition and metabolism to meet the bioenergetic, biosynthetic, and redox demands of malignant cells. These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. In this perspective, we provide a conceptual framework to understand how and why metabolic reprogramming occurs in tumor cells, and the mechanisms linking altered metabolism to tumorigenesis and metastasis. Understanding these concepts will progressively support the development of new strategies to treat human cancer.

Keywords: Cancer; ROS; glycolysis; metabolism; mitochondria; oncogenes.

Figures

Fig. 1. Signaling pathways that regulate cancer…
Fig. 1. Signaling pathways that regulate cancer metabolism.
Tumor cells have aberrant activation of mTORC1 that induces an anabolic growth program resulting in nucleotide, protein, and lipid synthesis. Loss of tumor suppressors like p53 or activation of oncogenes like MYC further promotes anabolism through transcriptional regulation of metabolic genes. Metabolism controls signaling through regulating reactive oxygen species (ROS), acetylation, and methylation. PPP, pentose phosphate pathway; G6P, glucose-6-phosphate; 3-PG, 3-phosphoglycerate; ATP, adenosine 5´-triphosphate; mTORC1, mTOR complex 1; α-KG, α-ketoglutarate; RTK, receptor tyrosine kinase.
Fig. 2. Metabolic pathways under nutrient-replete and…
Fig. 2. Metabolic pathways under nutrient-replete and nutrient-deprived conditions.
Accessibility to nutrients within solid tumors is regulated by proximity to the vasculature. Cells located adjacent to the vasculature use nutrients and oxygen to fuel anabolic pathways that support proliferation. However, cells distant from the vasculature have diminished accessibility to nutrients and oxygen and may engage in alternative forms of metabolism including oxidation of fatty acids and BCAAs as well as macromolecular degradation through autophagy and macropinocytosis to support cell viability.
Fig. 3. Anabolic pathways that promote growth.
Fig. 3. Anabolic pathways that promote growth.
Glucose metabolism generates glycolytic intermediates that can supply subsidiary pathways including the hexosamine pathway, PPP, and one-carbon metabolism, all of which support cell growth. Mitochondrial TCA cycle intermediates such as oxaloacetate (OAA) and citrate are used to generate cytosolic aspartate and acetyl-CoA for nucleotide and lipid synthesis, respectively. Mitochondria also generate H2O2 and acetyl-CoA for redox signaling and acetylation, respectively. NADPH is used to drive anabolic reactions and to maintain antioxidant capacity. Cytosolic sources of NADPH include the oxidative PPP, IDH1, and enzymes from one-carbon metabolism including MTHFD1. Mitochondrial sources of NADPH include MTHFD2, MTHF2L, and IDH2. HK2, hexokinase 2; G6PDH, glucose-6-phosphate dehydrogenase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LDH, lactate dehydrogenase; ACLY, ATP citrate lyase; GLS, glutaminase; SHMT, serine hydroxymethyltransferase; MTHFD2, methylenetetrahydrofolate dehydrogenase 2; MTHFD2L, MTHFD2-like; ACSS2, acyl-CoA synthetase short-chain family member 2; THF, tetrahydrofolate.
Fig. 4. Cancer cells maintain redox balance.
Fig. 4. Cancer cells maintain redox balance.
Cancer cells have increased rates of ROS production due to activation of oncogenes and loss of tumor suppressors that promote signaling pathways supporting proliferation and survival. However, cancer cells prevent the buildup of ROS to levels that incur damage by increasing antioxidant capacity through induction of NRF2-dependent genes and, in glucose replete conditions, the use of PPP to generate NADPH. As cells encounter hypoxia and low glucose due to limited vasculature accessibility, the levels of ROS further increase, requiring AMPK and one-carbon metabolism to enhance NADPH production to raise antioxidant capacity. Loss of matrix attachment and escape of cancer cells into the blood for dissemination to distant sites incur further increases in ROS levels, which require additional enhancements of antioxidant defenses to avoid cell death. It is important to note that too little ROS or too high steady-state ROS levels within cancer cells result in failure for solid tumor progression and metastasis.
Fig. 5. Relationship between glycolysis and oxidative…
Fig. 5. Relationship between glycolysis and oxidative phosphorylation in cancer cells.
(A) A common view of cancer cell metabolism invokes a switch from glucose oxidation in normal tissues toward glycolysis and suppressed oxidative phosphorylation (OxPhos) in cancer. (B) Analysis of metabolic activity in intact tumors from humans and mice argues against a switch. Rather, tumors appear to enhance both glycolysis and glucose oxidation simultaneously relative to surrounding tissue.

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