09 November 2017

Stop glycolysis

Cancerous tumors will be left without sweets

Anna Kaznadzei, N+1

Geneticists from the University of Colorado School of Medicine have found out that the CDK8 oncogene is involved in the regulation of several stages of glycolysis, and, apparently, is one of the important elements of switching the sugar metabolism of cancer tumors. A combination of drugs simultaneously aimed at inhibiting CDK8 and oxygen-free glucose breakdown can significantly reduce the chances of developing tumors in a number of oncological diseases, including colorectal and pulmonary. The study was published in Cell Reports (Galbraith et al., CDK8 Kinase Activity Promotes Glycolysis).

A growing tumor requires a lot of resources, and often, due to a lack of blood supply, it finds itself in oxygen-free conditions. At the same time, metabolism switches in its cells, known as the Warburg effect, during which the cell switches from oxidative processes in mitochondria (normal respiration) to oxygen-free glycolysis, and continues to work in this mode regardless of the presence of oxygen. As a result, the tumor consumes a lot of glucose, and this fact is used, for example, in oncological diagnosis and the search for tumors in the body using glucose isotopes and positron emission tomography (PET).

CDK8 gene expression is increased in a number of oncological diseases, including melanoma, breast cancer and colorectal cancers. A number of drugs have been developed against it, including Senexin A, but their action does not always have a positive effect. It was known that the work of CDK8 is necessary for cancer cells in conditions of hypoxia (lack of oxygen), but until now it was unclear exactly what processes it regulates.

Scientists subjected the CDK8 gene to genetic modification, as a result of which the action of its protein was inhibited when interacting with non-hydrolyzable ATP analogues (which were added to the medium). It was confirmed that inhibition of the protein leads to a decrease in the proliferation of cancer cells and their ability to form large tumors, which was observed both in colonies of cells growing on agar and when administered to experimental mice. In addition, it was found that CDK8 inhibition significantly affected the expression of a number of genes, among which genes activated under hypoxia and genes involved in the glycolysis process occupied significant positions. Using a fluorescent analogue of glucose, scientists have found that the modified cells have a significantly reduced ability to absorb and use this sugar.

Similar effects in terms of gene expression have been shown for a number of cancer cells and when using the anti-cancer drug Senexin A, which inhibits CDK8 without prior genetic modifications, however, there were a number of exceptions. So, in HCT116 cells, the GLUT3 glycolysis gene, which should have been inhibited, as it did in genetically modified cells in the experiment described above, on the contrary, was activated. Scientists suggest that this may be due to the dual effect of the drug on the CDK8 gene and its CDK19 paralog.

The next stage of the experiment was to study the viability of unmodified cancer cells of four different lines (HCT116 and SW480 colorectal cancer and A549 and H460 lung cancer), which were treated with Senexin A. It turned out that the viability of these cells decreases somewhat in the presence of oxygen, but does not change in hypoxia. The addition of 2-deoxyglucose inhibiting glycolysis effectively reduced the viability of all four lines under hypoxic conditions. For HCT116 cells, it was also shown that neither Senexin A nor 2-deoxyglucose affects the growth of spheroid formations separately, but their combination significantly disrupts it.

These results indicate that the combination of CDK8 inhibition and glycolysis may prove to be an effective strategy for combating tumor cells, in particular, colorectal cancers. Scientists believe that their research will serve as a basis for the development of a new type of drugs. 

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