New targets for cancer drugs are found

The beginning of the 20th century, the German physiologist Otto Warburg discovered that cancer cells do not eat as healthy as they do. Normally, the cell receives energy in the process of aerobic decomposition of glucose, as a result of which one monosaccharide molecule gives 36 cellular units of fuel – adenosine triphosphate molecules (ATP). Cancer cells use the mechanism of anaerobic glycolysis, which gives only two molecules of ATP.

This phenomenon, known as the Warburg effect, in theory, makes it possible to “starve” a cancer cell with famine: for this, it is only necessary to block substances important for the anaerobic process. True, attempts to do so have not been very successful so far. It was found that from the broad spectrum of enzymes involved in anaerobic glycolysis, lactate dehydrogenase A (LDHA) is most important for cancer cells. A substance that would block this enzyme in a living body has not yet been found.

Scientists from the Stanford-Burnham Medical Research Institute (USA) found that even if lactate dehydrogenase A is excluded from the metabolism of the skin tumour cell (melanoma) after a while glycolysis resumes – and the cancer cell recovers energy, grows and divides. Doctors also determined that another substance – the transcription factor ATF4 – comes to replace LDHA: the mutant cell soon switches to a signal pathway involving this substance and resumes vital activity.

After scientists blocked LDHA in melanoma cells, the latter stopped using ATP as an energy source: instead, they began to “eat” the amino acid glutamine. At the same time, the production of ATF4 increased noticeably in cells, due to which the flow of glutamine into the cell from the outside increased. The influx of amino acids, in turn, activated the production of the mTOR enzyme, a regulator of cell growth and survival, so that the cells continued to grow.

The research leader Gaurav Patria and his colleagues believe that simultaneous exposure to LDGA and mTOR can stop anaerobic glycolysis in melanoma cells, their growth and division, and even provoke the death of cancer cells. It makes sense also to try to block other enzymes involved in the metabolism of glutamine and the ERK signalling pathway for which there are effective inhibitors.

The data obtained by Patria and his colleagues not only suggest a new target for future medications for melanoma but also help to understand the reasons for the existence of the Warburg effect. “Perhaps the fact is that it is easier for cancer cells not to receive ATP, but to use for growth of an amino acid, and the rejection of aerobic glycolysis is due to this,” Patria explains.

The results of the study are published in the EMBO Journal.

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