Blood sugar, or glucose, is the main sugar found in human blood and plays an incredibly important role in the ability to create energy. As cancer cells are known to be able to rapidly consume large amounts of glucose, some have questioned if glucose may actually fuel the growth of cancer cells. To determine the exact role of glucose in cancer cell consumption and proliferation, researchers at the Washington University in St. Louis recently authored the study, "Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells" (Mol Cell 2022; doi: 10.1016/j.molcel.2022.07.007). Ultimately, their findings demonstrated that the speed at which glucose is transported is a major factor in its use for proliferation versus waste.
Important to note, cancer cell metabolism is distinct from most of the other healthy cells in the body, and one of the best-characterized examples of this stems from the rate at which cancer cells consume sugar glucose. Recognizing elevated glucose levels has therefore become a common way to diagnose and stage cancer in clinics.
Additionally, some have questioned if cancer cells can then be "starved to death" through glucose restriction. Gary Patti, PhD, the Michael and Tana Powell Professor at Washington University in St. Louis, shared that his team's research data suggests that, in fact, more glucose is consumed by cancer cells than can actually be processed in mitochondria, producing waste.
"A key question [was]: what does the 'extra' glucose do? Does it provide a little extra energy? Does it activate signaling processes? If excreting it as a waste product is inconsequential, then glucose restriction may not be an effective therapeutic target," Patti explained.
Study Details
To answer these questions, Patti and his fellow researchers first assessed aerobic glycolysis, also known as the Warburg Effect. This is when a cell experiences a high rate of glucose fermentation to lactate irrespective of oxygen availability. While this particular metabolic phenotype has been associated with rapidly dividing cancer cells, the researchers shared that, more recently, the process has been determined to be a general feature of most proliferating cells. If this is the case, the question remains: If the cells proliferate at such an increased pace, why would they waste glucose carbon?
"Ideas about the role of mitochondria in cancer have evolved over the past century. One of the first researchers to study cancer metabolism, Otto Warburg, argued that mitochondria are damaged in cancer," affirmed Patti. "Later work revealed that mitochondria are healthy and functional in tumors. The level of mitochondrial activity in cancer, however, has remained less clear. There has been this notion that cancer cells may prefer not to use their mitochondria when processing sugar. Our data suggest the opposite is true."
Patti added that cancer cells are unique from most other healthy cells in the human body because of their rapid proliferation. This means that the cells must replicate all of their cellular contents, a process that requires a lot of nutrients and energy. When cancer cells consume glucose at this rate, rather than processing it in their mitochondria (where the most amount of energy can be extracted), much of the glucose is now known to be released as waste.
Prior to his team's research-of which some of the data were obtained from previously published studies and other data generated in his university's own laboratory-at least three possibilities had been offered to explain aerobic glycolysis in cancer. First, it has been suggested that the rate of ATP production by fermentation may be faster than the rate of ATP production by mitochondrial respiration.
It has also been put forward that "aerobic glycolysis allows cells to divert glucose carbon to glycolytic branchpoints, thereby driving the flux of biosynthetic pathways essential for proliferation, such as one-carbon metabolism and the pentose phosphate pathway." A third hypothesis considered previously is that the limited physical volume of a cell may make producing energy from glycolysis, compared with oxidative phosphorylation, more spatially efficient.
"We tried to approach this project with an unbiased perspective by screening for metabolic attributes in cancer cells that were highly correlated with using glucose wastefully. This led us to our central hypothesis, which we tested in the rest of the study," Patti said. "Evaluating our proposed model involved two key types of experiments. First, we had to develop a strategy to measure the kinetics of the pathway of interest. Second, we manipulated the proteins involved in the pathway using."
According to Patti, the research was inspired by a screen looking at a panel of approximately 60 human cancer cell lines, many of which proliferate at different rates. He and his team suspected that more glucose would be wasted in the cell lines that proliferate faster. Yet, what they found was that the amount of glucose wasted was not related to proliferation. Rather, glucose was dependent on how quickly the cells could get glucose products into their mitochondria. Patti explained that, when the highways to feed glucose products into the powerhouse compartments inside cells were highly active, less glucose was wasted.
This discovery was made using metabolomics, the scientific study of the complete set of metabolites present within cells, biofluids, tissues, or organisms. Some examples of metabolites are glucose, cholesterol, and vitamins. In metabolomics, metabolites are most often measured by using mass spectrometers. The basic concept is that each metabolite can be distinguished on the basis of its different masses.
Further, the researchers combined metabolomics with stable isotope tracers, allowing them to identify different parts of glucose identification inside a cell. Once identified and tagged, the researchers could then observe the speed that glucose entered mitochondria or was excreted from cells. Through this methodology, Patti and his team discovered that the normal pathways for transporting fuel were becoming saturated within cancer cells.
"The goal of metabolomics is to measure the concentration of metabolites in a sample. While informative, this provides what is equivalent to a single photograph of metabolism," Patti explained. "Stable isotope tracing, on the other hand, allows us to track the rate at which a nutrient is transformed. Using the same analogy, this is like taking a movie of metabolism."
He also shared that, to appreciate when combining metabolomics with stable isotope tracers might be beneficial, consider an aerial photograph of a highway packed with cars. Patti explained that there are two reasons that the highway might be crowded:
1. It could be that there is an accident up ahead and all of the cars are sitting at a standstill.
2. It could be that the density of cars is high because it is rush hour, but all of the cars are going to the speed limit.
Metabolomics alone cannot differentiate between these possibilities. For that, stable isotope tracers are needed.
"Metabolites cannot pass freely in and out of mitochondria. Their passage is highly regulated, much like fans entering Yankee stadium must show a ticket to pass through the turnstiles. Right before game time, crowds accumulate outside the stadium because the turnstiles are too slow to let everyone in as fast as they are arriving," Patti explained. "The same thing happens with glucose. So much glucose is consumed by cancer cells that it can't all get into mitochondria fast enough. The 'turnstiles' that back up in cancer cells are called the malate-aspartate shuttle and the glycerol-3-phosphate shuttle."
He added that drawing an analogy between the principles of metabolism and traffic laws regulating cars on the street is helpful. For example, if cars could travel anywhere by any path at any time, it would be total chaos. Stop lights and traffic laws control who can go where and when. Patti explained that metabolism operates in much the same way.
"Traffic lights direct nutrients in specific ways, depending on the body's needs. For example, when a sugary drink is consumed while running a marathon, it is used to support muscle contraction. When a sugary drink is consumed after a huge meal in a state of minimal physical activity, it makes fat," he said.
Regarding research results, Patti believes that whether they are surprising or not likely depends upon who is asked. The metabolic paradigm he described is not new. However, he noted that it has not been rigorously examined in the context of cancer cells, while it is well established for other types of cells and tissues.
"Indeed, we usually assume that cells prefer to process glucose in their mitochondria rather than excrete it as a waste product," he said. "If you wanted to say something was surprising about our work, it might be that cancer cells are no different than other cells with respect to how they metabolize glucose. They seem to follow the same biochemical patterns."
Moving forward, Patti suggests there are two fundamental questions that still need to be addressed. The first involves why cancer cells consume so much more glucose than they can process in their mitochondria. He noted this may result from the "extra" glucose serving some biological function.
The second question is: What determines the speed at which the products of glucose metabolism can be transported into mitochondria? As his team's data show that different types of cancer cells have different set points, Patti proposes this could be a product of their nutrient environments (i.e., brain vs. liver).
"Notwithstanding, if we could better understand what limits the transport speeds, then this could potentially represent a therapeutic anticancer strategy," Patti concluded.
Lindsey Nolen is a contributing writer.
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