The Surprising Energy Metabolism of the Cancer Cell

Cancer cells are abnormal cells that can continuously divide and multiply. Characterized by their capacity for unlimited proliferation (division), transformation (change) and migration, these cells obtain the energy they need through unusual metabolic pathways to meet these demands. The main purpose of many carcinogenic signaling pathways is to control the 3 main metabolic pathways: glucose, lipid and amino acid metabolism.

Figure 1: The 10 Hallmarks of Cancer include reorganizing cellular energy in its own favor. Below are the 10 hallmarks of cancer and the types of cancer drugs developed against each:

4 Critical Concepts for Understanding Cancer Metabolism

The Warburg effect

First proposed by Otto Heinrich Warburg, the scientist awarded the 1931 Nobel Prize in Physiology or Medicine, the Warburg effect is the choice by tumor cells of lactic acid fermentation instead of the citric acid cycle and oxidative phosphorylation (aerobic respiration) that follow glycolysis in normal cells. Although this process, also called anaerobic (oxygen-free) respiration, is much less efficient for energy production, it offers tumor cells benefits such as producing side metabolites that support cell proliferation and preventing the production of free oxygen radicals that could damage the cell at high activity.

Figure 2: Cancer cells use glucose intensively in the pentose phosphate pathway and lactic acid fermentation. In other words, by processing glucose simply, they produce small amounts of ATP (energy) without needing much oxygen. Cancer cells tend not to put glucose into the Krebs cycle discussed below. They can, however, draw more glucose from the blood. One reason cancer cells direct glucose into the pentose phosphate pathway is to produce the ribose sugar needed to synthesize purine and pyrimidine nucleic acids. Nucleic acid synthesis is indispensable for these constantly dividing cancer cells. Another pathway, lactic acid fermentation, has a different function. By releasing the lactic acid they produce through this pathway into the intracellular space, cancer cells damage normal cells around them and thereby gain functions such as invasion (occupying surrounding tissue) and metastasis (occupying distant tissue). These cells also convert amino acids into acetic KoA in the Krebs cycle and use acetyl KoA to synthesize the fatty acids needed for cell growth and division.

New research has revealed that tumor cells achieve this effect through the enzyme 6-phosphofructo-2-kinase / fructose-2,6-bisphosphatase 4 (PFKFB4), which activates glycolysis, increases the transcriptional activity of steroid receptor coactivator-3 (SRC-3) and directs glucose into the pentose phosphate pathway. This explains why these tumor cells do not show active mitochondrial metabolism. The high glucose consumption of tumor cells makes this metabolic pathway a promising clinical treatment target.

Cancer cells have multiple metabolic signaling pathways, including redirecting glucose into aerobic respiration and continuing oxidative phosphorylation in the microenvironment. The regulatory changes cancer cells make to metabolic pathways extend beyond the Warburg effect. Investigating tumor metabolism is essential to better understand substances used in clinical interventions.

The Krebs cycle

Discovered by Hans Krebs, the scientist awarded the 1953 Nobel Prize in Physiology or Medicine, the Krebs cycle, also called the TCA cycle, is the process by which our cells pass pyruvate, the end product of glycolysis, through a cycle inside the mitochondria to produce NADH and FADH2. Of course, our cells do not use only glucose in this pathway. They also break down fats and amino acids and incorporate them at different steps of the cycle. The NADH and FADH2 molecules produced are then passed through the electron transport chain to produce ATP molecules, which we call oxidative phosphorylation.

This cycle, whose purpose at first appears to be simply producing ATP, has many different roles in cellular metabolism. Other functions include promoting cell death through cytochrome C release, generating an active immune response through mitochondrial DNA release, activating transcription factors by producing free oxygen radicals, and controlling cell signaling pathways through intermediate metabolites in the Krebs cycle. Given this, the Krebs cycle cannot be associated solely with energy production.

Figure 3: Krebs cycle metabolites have very important and different effects in physiology and pathology. Acetyl KoA, itaconate, succinate, fumarate and L-2-hydroxyglutarate can alter the response of both the innate immune system and the adaptive immune system. Functions such as the formation of new lymphatic vessels and maintenance of stem-cell pluripotency are associated with acetyl KoA and α-ketoglutarate, respectively. Succinate, fumarate and L-2-hydroxyglutarate are among the tumor metabolites that promote tumor formation. Succinate also acts as a systemic signal in regulating heat production during cold exposure.

As mentioned above, through the Warburg effect tumor cells tend to avoid the Krebs cycle. However, in some tumor types we see cells continuing this cycle in the microenvironment. This is because they use Krebs metabolites to activate the signaling pathways needed for division and growth.

Recent studies have shown that dichloroacetate stimulates mitochondrial oxidation, reduces the Warburg effect and interferes with tumor metabolism. This is a promising development in metabolic oncology.

Phosphorylation

Phosphorylation is a reaction known as the addition of a phosphorus group to chemical molecules. The organism uses this reaction to activate or silence molecules. Phosphorylation, actively used in normal cell metabolism, also has an important role in cancer metabolism. In vitro experiments in cervical cancer cells have shown that phosphorylated glucose-6-phosphate dehydrogenase (G6PD) keeps the pentose phosphate pathway active and sustains macromolecule synthesis. In breast cancer, AMP-activated protein kinase (AMPK) has been seen to phosphorylate and activate PFKFB4, directing the cell toward glycolysis instead of oxidative respiration.

Hypoxia

Tumor cells direct glucose into the anaerobic pathway of lactic acid fermentation regardless of the presence of oxygen in the environment. This was discussed above under the Warburg effect. Under hypoxic (low-oxygen) conditions, however, some enzymes enhance this effect. Hypoxia-inducible factor 1α (HIF-1α) is the transcription factor through which synthesis of molecules such as glucose transporter 1 (GLUT-1), pyruvate dehydrogenase kinase 1 (PDK-1) and lactate dehydrogenase A (LDHA) increases. GLUT-1 is involved in bringing glucose into the cell, helping it try to meet its increased glucose requirement. While the LDHA enzyme converts glucose to lactate, the PDK-1 enzyme inhibits pyruvate dehydrogenase (PDH). PDH is the enzyme that converts pyruvate to acetyl KoA and allows it to enter the Krebs cycle. As a result, through this HIF-1α released in hypoxia, tumor cells reinforce the Warburg Effect.

The 2019 Nobel Prize in Medicine was awarded for studies of how cells sense the presence of oxygen and adapt to hypoxia (low oxygen). Tumors also need to make good use of cellular mechanisms adapting to hypoxia in order to grow rapidly. From this idea came the possibility that drugs targeting tumor cells' mechanisms of adaptation to hypoxia could be effective in cancer treatment, and drug-development studies in this area began.

With a new, first-in-class small molecule, a hypoxia-inducible factor 2 alpha (HIF-2α) inhibitor, metastatic (stage 4) clear-cell kidney cancer in patients who had previously received multiple lines of treatment showed a significant anticancer response to the single agent. Results from this HIF2A inhibitor's phase I / II study were presented at the 2020 Genitourinary Cancers Symposium meeting.

Conclusion

Cancer metabolism research has seen major developments in recent years. However, these mechanisms and the genetic reasons behind them still require further research. New discoveries about cancer's reprogramming of metabolism may illuminate metabolic vulnerabilities that could become treatment approaches in the future. Together, we will see what science brings.