The Trifecta of Cancer: The Warburg Affect, p53 Mutation, and Altered Levels of SCO2
Devorah L. Segall
Brooklyn College
Abstract
The Warburg effect is described as cancer cells choosing glycolysis as the mode of cellular metabolism and has been a topic of interest for many years. (Kruse and Gu 2006). This is unique and intriguing based on glycolysis being the mode of cellular metabolism that yields very little energy, compared to aerobic respiration. Many researchers have delved into understanding p53, a tumor suppressor, and how mutations in p53 can lead to cancer. This led to the detection that p53 contributes to mammalian metabolism (Kruse and Gu 2006). Researchers have been attempting to understand how p53, which is involved in apoptosis and other methods of cell cycle control, can regulate the mode of cellular metabolism for energy (Kruse and Gu 2006). Matoba et al. (2006) hypothesized that a mutation in p53 can alter and affect the assembly of cytochrome c oxidase (COX) complex, which is vital to the process of aerobic respiration and utilization of oxygen in the mitochondrion. To demonstrate the Warburg effect, Matoba et al. (2006) revealed fatigue and premature exhaustion in mice that had mutated p53. Additionally, by analyzing liver cells of mice and human cell lines, the results of their experiment found that a deletion of p53 leads to the degradation of SCO2 (Synthesis of Cytochrome c Oxidase 2), which triggers cancer cells to rely on glycolysis. The findings of Matoba et al. (2006) demonstrates an additional hallmark of cancer (Kruse and Gu 2006); as cancer cells rely on glycolysis, tumorigenesis is promoted in hypoxic environments (Matoba et al. 2006). Additionally, this study provided insight on possible future cancer treatments, which involve the reactivation of p53 (Kruse and Gu 2006). Although this study was extremely thorough and precise, I believe the next step would be to analyze patients with cancers not due to mutated p53 and observe the mode of metabolism of the cancer cells and SCO2 levels.
A mutation in p53, a tumor suppressor, is the most common cause of cancer (Kruse and Gu, 2006). If there is damage done to DNA, p53 acts as a transcription factor and induces the necessary response (Kruse and Gu, 2006). Commonly, cancer cells have been found to undergo The Warburg Effect, which is defined as cancer cells using glycolysis as the chosen source for energy. In addition to only using glycolysis, cancer cells also decrease their aerobic respiration (Matoba et al. 2006). This is quite a conundrum as it would seem to benefit cancer cells more if they were to use aerobic respiration, which produces an abundance more ATP. Many researchers have studied p53 and its role in cancer, however, very few have studied the correlation between p53 and cellular respiration (Kruse and Gu, 2006). Understanding the precise mechanism as to how p53 affects mitochondrial aerobic respiration can bring great insight and contribute to the knowledge on how cancer cells behave, and ultimately how to treat cancer. Matoba et al. (2006) hypothesized that a mutation in p53 disturbs the cytochrome c oxidase (COX) complex and its protein subunits. The COX complex takes place in the mitochondrion of all eukaryotic cells and is critical for utilizing oxygen. Matoba et al. (2006) examined to understand the mechanism as to how p53 affects the COX complex since it is unclear. Matoba et al. (2006) observed oxygen consumption and the ATP production of mice and cell lines that were either homozygous or heterozygous for a loss of p53. The mice with a p53 deficiency were seen to have lower oxygen consumption levels, but ATP production levels did not vary among the control and experimental groups. By analyzing p53 expression, Matoba et al. (2006) believed the synthesis of cytochrome c oxidase 2 (SCO2) is dependent on p53. Analysis of mouse liver mitochondria and human cell lines revealed a decrease in SCO2 expression. Understanding the relationship between SCO2 and p53 can aid in targeted therapy and add to the vast knowledge of cancer behavior.
Firstly, Matoba et al. (2006) sought to evaluate The Warburg Effect by analyzing the oxygen consumption and ATP levels. This was conducted on liver mitochondria from mice that were either wild type (+/+), heterozygous (+/-), or homozygous (-/-) for a mutation in p53. The results indicated “there was a significant decrease in oxygen consumption that closely correlated with p53 deficiency” (Matoba et al. 2006). Moreover, ATP production did not change between the three mice groups, indicating “glycolysis compensates for the reduction in aerobic energy production” (Kruse and Gu, 2006). The mice were administered a swim stress test which revealed that the mice that lost p53 had a decrease in stamina. Additionally, levels of lactic acid production increased in the mice with p53 loss, further indicating glycolysis was being conducted and not aerobic respiration (Kruse and Gu, 2006). Combining all this information, “our results indicate that p53-/- mice exhibit decreased mitochondrial respiration, which could translate into a decrease in functional aerobic capacity” (Matoba et al. 2006).
Now that the correlation between p53 deficiency and glycolysis has been verified, the next step Matoba et al. (2006) took, was to determine how p53 regulated mitochondrial respiration. The prediction was “that a gene regulated by p53 might mediate this effect on mitochondrial respiration” (Matoba et al. 2006). Analyzing p53 expression revealed synthesis of cytochrome c oxidase 2 (SCO2), a subunit of the COX complex, as being dependent on p53. Confirmation that SCO2 is directly transactivated by p53 was conducted by examining SCO2 mRNA expression which resulted in “SCO2 mRNA expression increased within 3 to 18 hours of induced wild type p53 expression but was not affected by mutant p53” (Matoba et al 2006). SCO1 served as a negative control since it remained unchanged. Next, mitochondrial respiration regulation being affected by p53 through SCO2 was confirmed by disturbing “the SCO2 locus by homologous recombination in the human HCT116 cell line” (Matoba et al. 2006). Similar to the p53 deficient cells, the SCO2+/- cells showed an increase in glycolysis through the increase of lactic acid and a decrease in oxygen consumption. Moreover, the ATP levels stayed the same.
Whether the cells were heterozygous or homozygous for the deletion in SCO2, glycolysis was seen to be the mode of cellular respiration. This indicates “that p53 directly regulates mitochondrial respiration through SCO2” (Kruse and Gu, 2006). Furthermore, cells that were p53-/- had reduced levels of COX activity, again showing a direct correlation.
Cancer cells exhibiting The Warburg Effect is quite an enigma, but Matoba et al. (2006) sought to identify the exact mechanism as to how p53 plays a role in mitochondrial regulation. A direct correlation between aerobic respiration and p53 loss was found in the COX complex. It was established that p53 transactivates SCO2 expression, making it difficult for cancer cells to undergo aerobic respiration. Thus, cancer cells cannot rely on respiration that is mediated by p53, leaving glycolysis as the only option. However, this does not halt cancer cells in their production of ATP. As it was found, both p53-/- and SCO2-/- mice did not show a reduction in ATP production, indicating a compensation through glycolysis.
This connection between p53 and mitochondrial aerobic respiration adds to the knowledge of cancer behavior ultimately, cancer prevention. The actions of p53 and how it can downregulate many processes is a topic for further examination. Additionally, an inspection of SCO2 in cancer cells that do not have a loss in p53 is an important aspect to study.
Kruse and Gu (2006) suggest The Warburg Effect to be an additional hallmark of cancer. However, did not supply more evidence as to why this is the understanding. If it is to be another hallmark of cancer, it would be seen in all cancer cells, but whether this is the case or not, was not specified by Kruse and Gu (2006).
Additionally, Kruse and Gu (2006) mention the use of the Nutlin-3 drug to target p53 as a way of ensuring p53 is conducting the proper response to damaged cells, as well as using this drug to inhibit glycolysis and ultimately forcing the cancer cells into remission. Moreover, analyzing the SCO2 levels of cancer cells that proliferate due to causes other than p53 mutations and cellular metabolism can be the next step of research.
References
Kruse, J., & Gu, W. (2006). P53 aerobics: The major tumor suppressor fuels your workout. Cell Metabolism, 4(1), 1-3. doi:10.1016/j.cmet.2006.06.004
Matoba, S., et al. (2006). P53 Regulates Mitochondrial Respiration. Science, 312(5780), 1650-1653. doi:10.1126/science.1126863