Metabolic Sabotage: How Glycolysis Fuels Cancer Cells — Part 2 of 5
By Eva Fata
This is 2nd Part in a 5 Part Series I’ve written comparing cellular respiration in normal cells versus cancer cells. In this part, I will be exploring glycolysis in cancer cells. For all parts, please see the links at the bottom of this article.
One common alteration in cancer cells is their increased glucose uptake and fermentation of glucose to lactate. There is also an increase in glycolysis. This is seen in the presence of oxygen and normally functioning mitochondria. This is also known as the Warburg Effect.
Let’s dive into the Warburg effect
Otto Warburg was a German biochemist who was awarded the Nobel Prize for Physiology or Medicine in 1941 for his research on cellular metabolism. Warburg discovered that cancer cells or proliferating cells have altered metabolism, and have increased glucose uptake and fermentation of glucose to lactate, even in the presence of completely functioning mitochondria.
The metabolism of glucose like glycolysis allows for energy to be extracted in the form of ATP. This process is key for all mammalian life. The end product is lactate or CO2. However, in tumours, the rate at which glucose uptake happens is dramatically increased and lactate is produced. It is known that respiration alone could provide the ability for a tumour to survive. Along with that, it was later proposed that dysfunctional mitochondria are the root cause of aerobic glycolysis (Warburg Effect). Aerobic glycolysis was also proposed to have been a controllable process regulated by growth factor signalling.
Aerobic glycolysis is an inefficient way of producing ATP, compared to normal respiration. Despite this, the rate at which glucose is metabolized through aerobic glycolysis is higher because the production of lactate from glucose occurs 10–100 times faster than the complete oxidation of glucose in the mitochondria.
In aerobic glycolysis, glucose is metabolized through glycolysis which only produces a net gain of 2 ATP molecules per glucose molecule in the cytoplasm. Aerobic glycolysis provides a quick burst of ATP through glycolysis but the overall ATP yield is significantly lower compared to mitochondrial respiration. Therefore per unit of glucose, aerobic glycolysis is a rather less efficient way of generating ATP. This may seem weird but it allows cancer cells to rapidly produce ATP to support their high proliferation rate despite the lower energy yield compared to mitochondrial respiration.
The Warburg Effect has been proposed to be an adaptation mechanism which helps to support the biosynthetic requirement for uncontrolled proliferation. The increased glucose consumption creates a carbon source and is used to help the anabolic processes needed to support the proliferation. This carbon source is further used in the generation of lipids and proteins for the different products that originate from glycolysis.
The Warburg Effect is a specific observation in cancer cells which is their presence for aerobic glycolysis for energy production even in the presence of oxygen. Glycolysis on the other hand is a general metabolic pathway for breaking down glucose for energy which can occur in cancer and healthy cells. You can think of the Warburg Effect as a type of glycolysis cancer cells use.
Cancer cells can use glycolysis and oxidative phosphorylation for energy production. The Warburg Effect describes the preference for glycolysis but oxidative could be functional and contribute to ATP production in some cancers. The specific reliance on each pathway depends on the tumour microenvironment and the type of cancer.
I am going to group the Warburg effect into four different groups: Tumor microenvironment, Rapid ATP synthesis, Biosynthesis and Cell Signalling.
The Tumour Microenvironment
The Warburg Effect presents an advantage for cell growth in the cellular environment.
Metabolic Reprogramming in Cancer Cells: cancer cells use glycolysis for energy production even in the presence of oxygen. This adaption allows cancer cells to reach their increased demand for biosynthesis and energy for their rapid proliferation. Furthermore under these aerobic conditions pyruvate — the end product of glycolysis is usually transported into the mitochondria and used for oxidative phosphorylation. However, in cancer cells which exhibit the Warburg Effect, pyruvate is usually converted into lactate in the cytoplasm rather than being fully oxidized in the mitochondria
Acidosis: The overall acidification and other metabolic systems impacted can add even more advantages. The elevated glucose metabolism decreases the pH in the microenvironment due to lactate secretion. Acidosis in the tumour microenvironment is detrimental to normal cells but provides many benefits to cancer cells. Some benefits of acidosis for cancer cells is that it creates a microenvironment which blocks the function of immune cells which play a key role in eliminating cancer cells as well as stimulates the expression of pro-angiogenic factors the vascular endothelial growth factor (VEGF) which promotes the formation of new blood vessels to help support tumour growth and metastasis.
Nutrient Availability: Tumor cells compete for nutrients in a crowded and nutrient-depleted microenvironment. The glucose uptake and usage are increased in cancer cells to maintain glycolytic flux (the rate at which glucose is metabolized) and support cell growth and proliferation.
The Warburg Effect provides a general benefit which supports the tumor microenvironment which supports cancer cell proliferation. It is proposed that the Warburg Effect is rather an early event in oncogenesis, which is a consequence of an oncogenic mutation like KRAS in pancreatic cancer or BRAF in melanoma which occurs before cell invasion as well as in benign and early stages.
Targeting these metabolic vulnerabilities (processes which can make cancer cells susceptible to therapeutic interventions interrupting their metabolic pathways ) which are associated with the Warburg effect and tumour microenvironment is very promising for cancer therapies. Some therapies can be inhibiting glycolytic enzymes, disrupting lactate transport and disputing the metabolic dependencies that cancer cells have.
Rapid ATP synthesis
Aerobic glycolysis is rather an inefficient way of generating ATP compared to cellular respiration. However, the rate of glucose metabolism via aerobic glycolysis is much higher — the production of lactate from glucose happens 10–100 times faster than the complete oxidation of glucose in the mitochondria. Cancer cells need constant and rapid ATP production to help with their proliferation and growth.
So as you know cancer cells need lots of energy. They actually fight with other stromal cells for nutrients. So when they need more energy they increase their ATP demand and make ATP pumps work harder in hopes of getting more ATP. Therefore aerobic glycolysis increases rapidly as it’s quicker, similar to taking a shortcut. Now think would you rather run a marathon to get something you love or just a quick sprint? This is what cancer cells think about when they want more energy and ATP. They choose aerobic glycolysis (sprint) rather than oxidative phosphorylation (marathon) because it’s a fast way of making ATP and getting the energy they need for proliferation and growth but it’s not as efficient and is not sustainable for a long time.
There have been findings which indicate that the relationship between ATP demand and tumour growth is more complex than researchers originally thought. Tumour cells do grow rapidly, but the ATP requirements for growth may not be as significant then previously assumed. Nevertheless, tumour cells still take up lots of energy. Tumour cells actually have a mechanism to regulate their ATP production similar to what normal cells have which suggests that ATP availability may not be a limiting factor in tumour progression. These findings change perspectives on the role of ATP and tumour biology and could be further researched into the metabolic dynamic of tumour cells.
Rapid ATP Synthesis Mechanisms
While you exercise, cells need sudden bursts of energy and they have these specific mechanisms which help them meet that demand quickly. One of these mechanisms involves enzymes called creatine kinases or adenylate kinases. These enzymes help cells to rapidly generate ATP when there is a sudden need for energy (like exercising). It is similar to having emergency generators that kick in when the power goes out.
Interestingly, these mechanisms are also found in most tumour cells. This means that tumour cells also have the tools which are needed to quickly produce ATP when necessary just like other cells have. However despite having these rapid ATP synthesis mechanisms tumours still heavily rely on aerobic glycolysis. This is quite puzzling for researchers because the cells have other mechanisms at their disposal. More research is needed to understand why tumour cells prefer aerobic glycolysis rather than other efficient ATP synthesis pathways.
Biosynthesis
The Warburg Effect is an adaption mechanism which is used by tumour cells to help support their high demand for building blocks lipids, and proteins (biosynthesis) which are needed for uncontrolled cell proliferation. Furthermore, tumour cells consume a lot of glucose compared to normal cells. However rather than just using it for energy, they use it for anabolic processes needed to help them grow and multiply. Additionally, this excess glucose they consume serves as a source of carbon atoms which can be used in the production of new building blocks like nucleotides, lipids and proteins and also other molecules which are produced during glycolysis can be diverted into other pathways. These pathways branch off from glycolysis and further lead to the production of different molecules needed for cell growth and division. This is similar to having a side road which branches off from a main highway and leads to different destinations.
One example of how the Warburg Effect supports biosynthesis is through the enzyme phosphoglycerate dehydrogenase (PHGDH) which diverts the glycolytic flux (flow of molecules through the glycolysis pathway) into de novo serine biosynthesis. This means instead of only using glucose for energy tumour cells use it to make serine which is an amino acid needed for building proteins and other molecules.
Tumour cells have a higher need for reducing equivalents mostly in the form of NADPH, which is needed for different biosynthetic processes. By taking in more and more glucose and using the oxidative branch of the pentose phosphate pathway tumour cells can then produce more NADPH. The NADPH is then further used for reductive biosynthesis, including the production of new lipid synthesis which is important for building many structures including the cell membrane.
Another way the Warburg Effect supports biosynthesis is the rapid regeneration of NAD+ from NADH during the conversion of pyruvate to lactate which is the step that completes aerobic glycolysis. This is important because it allows glycolysis to continue at a rather high rate. This rapid glycolysis allows for intermediates such as 3-phosphoglycerate (3PG) which could be used for biosynthetic pathways like serine synthesis which contributes to NADPH as well as nucleotide production.
Cell Signalling
The Warburg Effect has been proposed to have direct signalling functions within the tumour cells. This suggests that the altered glucose metabolism directly influences signalling pathways within tumour cells and affects different cellular processes which further contributes to tumorigenesis.
I will be talking about two areas of signalling functions modulation of reactive oxygen species and modulation of the chromatin state
- Generation and modulation of reactive oxygen species (ROS). ROS are molecules which contain oxygen and are very important for cell signalling. Excessive ROS can damage cell membranes and nucleic acids. Insufficient ROS can disrupt signalling processes which are important for cell proliferation and growth. One example is it can inactive proteins such as phosphatase and tensin homolog (PTEN) and tyrosine phosphates which are involved in regulating cell growth and survival. The Warburg Effect causes different alterations which can change ROS levels and affect various cellular processes and components.
2. Modulation of Chromatin state: The Warburg Effect also impacts the structure of the chromatin which can further influence gene expression and cell behaviour. Glycotic metabolism has also been shown to have an impact on chromatin structure.
The Warburg Effect can change ROS production, these changes in the ROS levels can further influence cellular signalling pathways and contribute to the development and progression of cancer.
Other Effects of the Warburg Effect on Cell Signalling
NADH and Redox Balance
NADH is a coenzyme which carries high-energy electrons produced during glycolysis and citric acid cycle to the electron transport chain in the mitochondria. The redox potential (chemical species to acquire electrons and undergo reduction) is determined by the balance of NADH and NAD+ which influences cellular processes like metabolism and signalling. This is essential for maintaining cellular function and preventing oxidative stress. The Warburg Effect can disrupt this balance which can affect metabolism and cell signalling.
Warburg Effect and Oncogene-induced Senescence (OIS)
The Warburg Effect is a preference cancer cells have for glycolysis rather than oxidative phosphorylation even in the presence of oxygen. Oncogene-induced senescence (OIS) prevents the proliferation of cells with activated oncogenes which acts as a tumour suppressor. Some studies suggest that alteration in NADH balance because of increased glycolysis can play a role in the regulation of OIS. Particulary increased glucose oxidation through the pyruvate dehydrogenase (PDH) may alter OIS by influencing NADH levels and redox balance.
Histone Modifications and Gene Expression
Glucose metabolism, particularly glycolysis can influence histone modification like acetylation and methylation which regulate chromatin structure and gene expression. Acetyl-CoA which is a key metabolite derived from glucose metabolism, serves as a substrate for histone acetylation. Changes in histone acetylation patterns can affect the accessibility of DNA transcription factors and RNA polymerase which can influence gene expression profiles which are associated with cancer cell growth and survival. This link between glucose metabolism and histone modification shows how the Warburg Effect can impact gene regulatory networks which are involved in tumorigenesis.
Nutrient Sensing and Signaling
Glucose metabolism regulates nutrient sensing and signalling pathways which control cell growth and metabolism. Nutrient availability influences the activity of signalling molecules like AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) which combine metabolic and signalling cues to regulate their cellular responses. The Warburg Effect alters nutrient availability and metabolic signalling pathways which affect cell growth, proliferation and survival.
Consequences of the Warburg Effect
The changes which happen in the glucose metabolism not only impact energy production but also the regulation of cellular processes like redox balance and gene expression.
So why should we learn about the Warburg Effect?
By targeting the Warburg Effect in cancer cells there are several therapeutic potentials which could help treat and prevent cancer. Some possible therapeutic interventions could be developing drugs which target specific enzymes which are involved in glycolysis like hexokinase which could disrupt cancer cell metabolism.
Next Articles in The Series
To explore the previous parts of the series: Part 1
To explore the next parts of the series: Part 3, Part 4, Part 5
Sources:
https://www.nobelprize.org/prizes/medicine/1931/warburg/biographical/
https://www.sciencedirect.com/topics/medicine-and-dentistry/warburg-effect
