Glycolysis or oxidative phosphorylation?

Energy production is a cellular response to the demand for energy. Therefore, cellular ATP production varies depending on the state of the cell and the surrounding environment. Currently, cells rely on two main pathways, glycolysis and oxidative phosphorylation (OXPHOS), to produce ATP. The proportion of these two energy-producing pathways in cellular energy production also varies depending on the environment and the cell. Normal cells, in the presence of oxygen, rely mainly on OXPHOS to produce ATP, a process that provides 70% of the energy required for cellular metabolism. In contrast, it is under hypoxia that glycolytic activity is enhanced and used to compensate for the reduced OXPHOS function due to hypoxia. Thus, it is glycolysis and OXPHOS that work together to maintain cellular energy homeostasis.

The energy metabolism of normal cells is characterized by OXPHOS using glucose in the mitochondria, which is both economical and efficient. Tumor cells differ significantly from normal cells in their energy metabolism. They can increase glucose and glutamine uptake and perform aerobic glycolysis, resulting in high lactate and low ATP production. However, tumors are heterogeneous, and each tumor has its own metabolic characteristics. Even different tumor cells within the same tumor differ in their metabolic patterns. The metabolic patterns of tumor cells are not invariable, but constantly change with the changes of microenvironment, the purpose of which is to enable tumor cells to maintain a selective growth advantage in an unfavorable survival environment.

Not all tumor cells exhibit glycolysis due to different cellular origins and differentiation degrees, and the contribution of glycolysis to the total ATP of tumor cells varies from 1% to 64%. The energy metabolic pathways of different tumors are different. When anti-metabolic drugs are selected to treat tumors, the energy metabolic pathways of tumors should be examined first so as to achieve better therapeutic effects.

Why do tumor cells prefer to use aerobic glycolysis as their main metabolic pathway even though they retain OXPHOS function? The main reasons are as follows: (1) Glycolysis is more suitable for the growth of tumor cells. Tumor growth is more rapid than normal tissue, and it requires not only energy but also biomolecules needed for growth. The intermediate products of glycolysis or the truncated TCA cycle can be used by tumor cells to synthesize nucleotides, lipids and proteins. (2) Although glycolysis produces less ATP than OXPHOS, it can produce ATP more rapidly than OXPHOS, which is well suited to the needs of fast-growing tumor cells. In general, fast-growing cells are more dependent on glycolysis than slow-growing cells, while differentiated cells are dependent on OXPHOS.

In addition to glucose as the primary energy supplier for most tumors, researchers have found that glutamine metabolism (glutaminolysis) may be an additional energy replacement pathway for some tumors because of the high glutamine consumption characteristic of tumor cells.

Why do tumors appear to metabolize energy in different ways?

Tumors are a heterogeneous group of diseases, and it is not surprising that their genotypes are so different that their metabolic phenotypes differ. Even the same tumor shows differences in metabolic phenotype depending on the tumor cells that constitute it. Such different cell subpopulations within the same tumor can form complementary relationships in metabolism, forming metabolic symbioses.

Tumor cells undergo continuous reprogramming in response to environmental stresses and changes in their growth state during evolution to adapt to changes in their environment. The ratio of glycolysis to OXPHOS contribution to the output of ATP, the ratio of glucose to glutamine contribution to the output of ATP, or the ratio of glucose/glutamine to fatty acid contribution to energy are constantly changing, and these changes result in maintaining the selective growth advantage of tumor cells.

Creative Proteomics can provide customers with metabolite assays in energy metabolism to accelerate the progress of related research.

Reference

1. Kim, S. Y. (2018). Cancer energy metabolism: shutting power off cancer factory. Biomolecules & Therapeutics, 26(1), 39.