Role of OXPHOS during Glucose Metabolism in Cancer Development
Cancer is a complex disorder that results from alterations in either oncogenes or the tumour suppressor genes in the body of an organism. An important hallmark of cancer cells is the reprogramming of metabolic processes that occur within them. They have altered mechanisms for the metabolism of sugar, proteins, and fats.
The glucose metabolism in cancer cells differs from that in normal cells. They have increased rates of growth and proliferation, and hence they require an increased amount of energy as well so that they can perform basic survival activities. However, the amount of glucose in the cell to produce energy is insufficient for malignant cells to meet their energy demands. Hence, they take up glucose from the environment outside the cell and utilize it for energy production to survive and progress.
Glucose metabolism in cancer cells
The reprogrammed metabolism of sugar has been observed in malignant cells as they require large amounts of glucose to be metabolized and converted into ATP energy for their survival and all the basic signalling pathways in the cells which are also dependent on the energy needs.
The cancer cells have the essential characteristic that they prefer the glycolytic process over the Oxidative phosphorylation even if oxygen is plentiful in the cells. These cells convert pyruvic acid, the end product of the glycolytic pathway, into lactic acid which is very crucial for the survival and progression of cancer (Shaw, 2006).
Warburg proposed that the cancer cells can continue glycolysis even in the presence of oxygen and do not go for OXPHOS that occurs in the mitochondria. This was termed aerobic glycolysis and also called the Warburg effect. In this case, malignant cells take up glucose from the extracellular space with the help of specific glucose transporter proteins found in the plasma membranes of these cells in excess and metabolize this glucose by glycolytic pathway converting it into pyruvate by multiple steps involving different catalytic proteins or enzymes.
This pyruvate is then converted into lactic acid. This process produces only 2 ATP molecules. However, in mitochondria, if pyruvate is converted to energy by the process of OXPHOS, the amount of ATP energy is much greater compared to this. Almost 36 ATP molecules are produced as net energy through this process. But cancer cells mostly prefer glycolysis in the cytosol over this. So, basically unlike normal body cells, cancer cells do not convert pyruvic acid into energy in the mitochondria by the TCA cycle and oxidative phosphorylation process (Zheng, 2012).
OXPHOS in cancer cells
Although it was found earlier that the malignant cells do not produce energy by OXPHOS in the mitochondria, instead, they take up glucose from the exogenous environment and keep on converting it into lactate by the aerobic glycolytic process. But later the experimental findings have shown that the cancer cells have metabolic changes in the mitochondria as well.
The oxidative phosphorylation process does take place in the cancer cells because of the availability of many substrates required for this process to occur in the mitochondria. In most cases, it has been observed that the lactic acid produced in the cytosol that is mostly transported in the TME to make the environment around cancer cells acidic for their angiogenesis and survival, is transported to the mitochondria, where it is oxidized to form the pyruvic acid and then the TCA cycle starts in the mitochondria and so energy is produced by OXPHOS that is then utilized by the cancer cells for multiple purposes (Solaini et al., 2011).
Substrates for OXPHOS
Many experiments have shown that in malignant cells, many of the substrates are available in the mitochondria. Moreover, when there is a limitation of glucose concentration in the cancer cells, they utilize these substrates to start the process of oxidative phosphorylation and get the energy they are looking for. Many of the substrates have been observed when working on cancer cell lines in the laboratory, that are present in the mitochondria and help the cancer cells produce energy by OXPHOS.
It is found that about 40 to 75% of the energy needed by cancer cells for their survival and progression is produced by the conversion of glucose to pyruvic acid and then to lactic acid while the remaining energy required by these cells comes from the OXPHOS occurring in mitochondria by utilizing substrate molecules of the process (Zheng, 2012). Some of these substrates are discussed below.
An experiment was performed on the Hella cell lines in the laboratory. The cell lines were given glutamine in the place of glucose, and it was observed that the cells started producing energy by OXPHOS instead of aerobic glycolysis. This occurs in the mitochondria, glutamine forms alpha-ketoglutarate in the mitochondria by a trans aminase reaction and this alpha-ketoglutarate is a very crucial part of the TCA cycle. So, the TCA cycle produces NADH and FADH that are then converted to ATP by the electron transport chain in the cell mitochondria.
So, alpha-ketoglutarate produced by the transamination of glutamine can act as a substrate for oxidative phosphorylation. This mostly occurs in the tumor cells when there is a less concentration of glucose in the extracellular environment or when there are not enough glucose transporters in the plasma membranes of these cells so that they are unable to metabolize glucose by aerobic glycolysis. Then, these cells go for oxidative phosphorylation to make sure their survival and produce energy by this mechanism under such conditions (Sica et al., 2020).
Acetate or acetic acid can also help the cancer cells produce energy when their survival becomes difficult in the absence of enough amount of glucose. Acetyl groups are the building blocks for the synthesis or production of fatty acids and lipids in the cytosol of cells. These are also produced by the beta-oxidation of fats when these are degraded. The degradation of fats results in the formation of acetyl groups in the mitochondria. These acetyl groups are converted to acetyl coAs by the addition of coenzyme A and become part of the tricarboxylic acid cycle thus starts producing energy by oxidative phosphorylation.
So, we can say that when cancer cells do not have enough glucose to meet their energy needs, the mechanism of OXPHOS in these cells plays a crucial role in the development of carcinoma and its progression.
Pyruvate that is produced by other sources than glycolysis is also used by the malignant cells as a substrate for the OXPHOS. For example, it can be produced by the transamination of alanine amino acid and is then converted to the components of the TCA cycle in the mitochondria. The NADH and FADH produced during TCA provide energy for cancer cells’ survival.
Pyruvate can also be produced by many other sources in the mitochondria and used as a substrate of OXPHOS by cancer cells under energy-depleted conditions. So, the cancer cells become dependent upon the energy that is produced by OXPHOS for their survival under glucose-scarce conditions.
Lactic acid is found in excess in the tumor cells as well as in the environment around these cells. It is produced by the primary energy-producing mechanism in the malignant cells as a by-product. It helps cancer cells in multiple ways. The most important advantage cancer cells get from lactic acid is that it makes their extracellular environment acidic and helps in angiogenesis as well as metastasis thus helping them in the progression of malignancy.
When glucose is not enough for the cancer cells to undergo the glycolytic process and produce energy, then they use the lactic acid in their mitochondria and oxidize it to form pyruvic acid that enters the TCA cycle and provides the cancer cells energy by oxidative phosphorylation mechanism (Marini et al., 2016).
So, these are some of the most commonly available substrates used by cancer cells to produce energy by the process of oxidative phosphorylation. These cells are dependent on this process for their survival and growth when they have a depletion of glucose for aerobic glycolysis. So, the process of oxidative phosphorylation is very crucial in the development and growth of malignant cells.
Cancer cells have reprogrammed sugar metabolism, and they usually prefer glycolysis over oxidative phosphorylation even if oxygen is plentiful. But if there is a limited concentration of glucose then they need some other energy-producing mechanism for their survival.
Substrates of oxidative phosphorylation have been found in the mitochondria of the malignant cells that can go into the TCA cycle and help the cells produce energy for their growth and proliferation. So, in such conditions, cancer cells become dependent on OXPHOS for their survival.
Marini, C., Ravera, S., Buschiazzo, A., Bianchi, G., Orengo, A. M., Bruno, S., Bottoni, G., Emionite, L., Pastorino, F., Monteverde, E., Garaboldi, L., Martella, R., Salani, B., Maggi, D., Ponzoni, M., Fais, F., Raffaghello, L., & Sambuceti, G. (2016). Discovery of a novel glucose metabolism in cancer: The major role of endoplasmic reticulum in glycolysis and pentose phosphate shunt. Scientific Reports, 6(January), 1–13. https://doi.org/10.1038/srep25092
Shaw, R. J. (2006). Glucose metabolism and cancer. Current Opinion in Cell Biology, 18(6), 598–608. https://doi.org/10.1016/j.ceb.2006.10.005
Sica, V., Bravo-San Pedro, J. M., Stoll, G., & Kroemer, G. (2020). Oxidative phosphorylation as a potential therapeutic target for cancer therapy. International Journal of Cancer, 146(1), 10–17. https://doi.org/10.1002/ijc.32616
Solaini, G., Sgarbi, G., & Baracca, A. (2011). Oxidative phosphorylation in cancer cells. Biochimica et Biophysica Acta – Bioenergetics, 1807(6), 534–542. https://doi.org/10.1016/j.bbabio.2010.09.003
Zheng, J. (2012). Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (review). Oncology Letters, 4(6), 1151–1157. https://doi.org/10.3892/ol.2012.928
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