Cell metabolism in non-small-cell lung cancer

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Lactate, a molecule well known for its role in metabolism, is also linked with progression of some cancers, including non-small-cell lung cancer (NSCLC). Dr Yanyan Ma, Department of Scientific Research, Affiliated Hospital of Qinghai University, China, explores this further. She has observed that lactate may be able to regulate cellular metabolism by changing the way the body reads its genetic code. Understanding more about how lactate changes cell metabolism in normal and cancerous cells may improve treatment options and the prognosis for patients with NSCLC.
Non-small-cell lung cancer (NSCLC) is the most common form of lung cancer, a disease which accounted for 12% of all new cancer diagnoses in 2020. Although treatments have progressed over recent years, prognosis is still poor, with less than 17% of patients surviving five years after diagnosis.

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Metabolism refers to the chemical (metabolic) processes that take place as your body converts foods and drinks into energy. It’s well established that cancer cells change metabolic processes within the cells of the human body. For example, cancer cachexia, or wasting syndrome, can occur when the body uses up calories faster than normal due to a shift in metabolic processing. At a molecular level, cancer cells may change how genes are expressed to shift metabolic processes in their favour, for example by increasing energy production to meet the needs of the rapidly proliferating tumour cells. One molecule that has already been shown to influence cellular metabolism in NSCLC is lactate.

“Non-small-cell lung cancer (NSCLC) is the most common form of lung cancer.”

Feel the burn

Lactate is a molecule produced by a variety of cell types, including muscle cells, red blood cells, and brain cells. It’s produced during energy production via anaerobic metabolism, and occurs in the absence of oxygen. Although aerobic metabolism is the body’s preferred way of generating energy, this requires an adequate supply of oxygen. When oxygen levels are low, the body changes the way it uses (metabolises) glucose, and lactic acid (or lactate) is produced.

The type of lung cancer that develops depends on the type of cell the cancer starts in: small-cell or non-small-cell. Scio21/Shutterstock.com

An accumulation of lactate in the blood can cause serious health complications as it may alter the carefully regulated pH balance within the body. A mild increase in lactate is also seen during intense exercise and can be the reason we feel our muscles burning as we pass a certain threshold.

However, the precise roles of lactate in human metabolic disease are still being uncovered. Dr Yanyan Ma is part of a team from the Department of Scientific Research, Affiliated Hospital of Qinghai University, China. The team’s research focuses on metabolic diseases, particularly how they may present at high altitudes.

There is a link between cancer cells and lactate known as the Warburg effect. This term was first coined when a scientist called Otto Warburg noticed that tumour cells produced large amounts of lactate, even when there is sufficient oxygen available. Alongside this, low oxygen levels frequently develop during tumour growth, especially within solid tumours, as the tumour cells grow and divide so quickly that they outgrow their blood supply, leaving internal areas of the tumour with lower than normal oxygen provision.

When oxygen levels are low, the body produces lactate when it uses (metabolises) glucose.

Lactate acts as fuel for the tricarboxylic acid (TCA) cycle in human lung cancer, the main process by which cells obtain energy when there is adequate oxygen available, and can also promote disease progression. Previous studies using models of different cancers have shown the importance of lactate, as cancer cell proliferation was supressed when cells were not able to use lactate in their normal manner.

X-ray image of the chest shows non-small-cell lung cancer on the right side (opaque area denoted by red star). Good Image Studio/Shutterstock.com

It has also been shown by other researchers that lactate may cause magnesium to be released from structures inside human cells. Once the magnesium is released, it is taken up by the energy-producing powerhouses of the cell, the mitochondria. This uptake of magnesium can inhibit the activity of the mitochondria, something that may be important if oxygen (the usual fuel used by mitochondria) levels are dropping.

There is another way that lactate may help cells adapt to low oxygen levels, in this case by binding to certain proteins within the cell to protect them from being degraded when oxygen levels fall.

The genetic language

Lactate may be able to alter which genes are expressed within NSCLC cells. This is a form of epigenetic modification, which changes how the body can read a DNA sequence, despite no change to the original, underlying DNA sequence. Think of this as reading a sentence in a different language; the message remains the same although it sounds different and can be understood by a different group of people. For example, smoking can change which version of a particular gene is expressed and this may play a part in the development of diseases associated with smoking.

Microscope image of a non-small-cell carcinoma (dark blue cells). David A Litman/Shutterstock.com

One epigenetic change involves histones, proteins which DNA is wrapped around, like a spool. During periods of stress, such as low oxygen levels, an extra lactate group may be added to the histone (a process called lactylation). This changes the structure and function of the histone and consequently changes the way the genetic information linked to the histone is read.

Metabolic changes in non-small-cell lung cancer

Ma and colleagues explored the effect of lactate on mitochondrial function and cell metabolism in human NSCLC cells. They used NSCLC cells obtained from patients at the Affiliated Hospital of Quinghai University and used fluorescently labelled antibodies to identify molecules expressed by the cells. In addition, laboratory-grown cells (normal lung cells and lung cancer cells) were used to explore how cells responded to increasing levels of lactate and varying oxygen conditions.

Ma and colleagues show that the regulation of cellular metabolism by lactate in human NSCLC is likely caused by histone modifications, leading to changes in gene expression. Art of Science/Shutterstock.com

The study showed that there were metabolic changes associated with NSCLC, including an increase in genes involved in lactate production and transport. There was also an association between increased levels of metabolic enzymes, aberrant lactate metabolism, and a poorer prognosis, suggesting that lactate does have a significant impact on disease progression. This may be due to the impact that lactate has on the proliferation and migration of NSCLC cells, as the results also showed lactate could influence different parts of the cell-growth cycle. Ma found that lactate altered metabolism under both normal and low oxygen levels, as would be seen inside a solid tumour. Glucose uptake by cells was suppressed, as was the conversion of glucose into other intermediate molecules involved in energy production. Interestingly, the researchers found that mitochondrial balance was maintained, although there were some shifts in activity. This is likely due to the importance of the mitochondria for converting glucose into energy for the ever-hungry cancer cells to use. The researchers concluded that the regulation of cellular metabolism by lactate in human NSCLC was likely caused by histone modifications leading to changes in gene expression.

“Lactate may be able to alter which genes are expressed by NSCLC cells.”

Future directions

Understanding disordered metabolism in lung cancer may help improve the ways in which tumours are classified, as well as the discovery of potential therapeutic targets. Although the link between lactate and progression of human lung cancer is well known, the effect of lactate on lung cancer metabolism is less clear. While Ma concludes that lactate does influence cellular metabolism through changes in enzymes and gene expression, she highlights that further studies are still required to explore the ways in which histone lactylation can cause both increases and decreases in gene activity and metabolic pathways.

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If scientists can find a way to disrupt the energy supply to tumour cells, this may be an effective treatment for cancer. These findings could also be applied to other disease conditions linked with increased production of lactate or the Warburg effect, such as infection, sepsis, or autoimmune conditions.

In the meantime, understanding more about the mechanisms behind NSCLC both advances the scientific field and offers new opportunities for novel treatments to combat one of the most common cancers in the world.

Can you tell us more about the other metabolic disorders that your research focuses on?
Our future work will mainly focus on two aspects. Firstly, to confirm the roles of lactate-regulated genes identified via RNA sequencing in NSCLC cellular activities and their underling molecular mechanisms. Secondly, we will explore the link between lactate and lipid metabolism in NSCLC cells.

 

References

  • Jiang, J, et al, (2021) Lactate modulates cellular metabolism through histone lactylation-mediated gene expression in non-small-cell lung cancer. Frontiers in Oncology, 11, 647559. doi.org/10.3389/fonc.2021.647559
DOI
10.26904/RF-143-3258429491

Research Objectives

Dr Yanyan Ma explores the effect of lactate on glycolysis and mitochondrial function.

Funding

  • Science and Technology Agency of Qinghai Province
    (No 2022-ZJ-719)
  • Qinghai Health Committee (No 2020-wjzd-03)
  • Science and Technology Agency of Qinghai Province
    (No 2021-ZJ-977Q)

Bio

As ‘Academic Leader of Qinghai Province Natural Science and Engineering Technology’ and ‘Leading Talent in Kunlun Elite, High-End Innovation and Entrepreneurship Talents’, Dr Ma completed her postdoctoral work in Peking University, and has been concentrating on diagnosis, treatment, and pathogenesis of inherited metabolic disorders in mitochondria and organic acids, including amino acids and fatty acids.

Dr Yanyan Ma

Contact
Affiliated Hospital of Qinghai University, Tongren Road 29, ChengXi District, Xining, Qinghai Province, China, 810000

E: xnmayanyan@126.com
T: +86 0971 6162010
W: www.qhuah.com

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