The Warburg Effect against melanoma

New targets for cancer drugs found

Ksenia Malysheva, Naked Science

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

This phenomenon, known as the Warburg effect, in theory allows you to "starve" a cancer cell: for this you only need to block substances important for the anaerobic process. However, so far attempts to do this have not been very successful. It was found that of the wide range of enzymes involved in anaerobic glycolysis, lactate dehydrogenase A (LDHA) is the most important for cancer cells. A substance that would block this enzyme in a living organism has not yet been found.

Scientists from the Stanford-Burnham Medical Research Institute (USA) found out that even if lactate dehydrogenase A is excluded from the metabolism of a skin tumor cell (melanoma), after a while glycolysis resumes – and the cancer cell receives energy again, grows and divides. Doctors also found that another substance comes to replace LDHA – the transcription factor ATF4: the mutant cell soon switches to the signaling pathway with the participation of 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 significantly increased in the cells, due to which the intake of glutamine into the cell from the outside increased. The influx of amino acids, in turn, activated the production of the enzyme mTOR, a regulator of cell growth and survival, so that the cells continued to grow.

The head of the study, 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 also makes sense to try to block other enzymes involved in the metabolism of glutamine and the ERK signaling pathway, for which there are effective inhibitors.

The data obtained by Patriya and his colleagues not only suggest a new target for future melanoma drugs, 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 get ATP, but to use amino acids for growth, and the rejection of aerobic glycolysis is due to this," explains Patria.

The results of the study are published in EMBO Journal (Pathria et al., Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival).

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