Goddess of Fate against glioblastoma

Scientists have identified a gene mechanism that stops the development of a malignant brain tumor

UrFU Press Service

Yekaterinburg scientists have revealed that the Kloto gene is able to suppress the growth of glioblastoma cells — a malignant tumor of the brain and spinal cord. The conducted experiments contribute to the development of new methods for the diagnosis and treatment of glioblastoma and were carried out with the support of the Ministry of Health of the Russian Federation. An article describing the studies and their results was published in the Journal of Molecular Neuroscience (Melekhin et al., Investigation of the Role of Induced Overexpression of the Isolated Secreted Klotho on the A-172 Human Glioblastoma Cells).

In the active state, the Kloto gene (Kloto is the goddess of fate in ancient Greek mythology) produces two forms of protein (it is also named after the goddess Kloto) — longer transmembrane and truncated secreted. The transmembrane form of the protein is embedded in the membrane of a single cell and acts directly on it. The secreted form is released by the cell into the intercellular space, enters the bloodstream and spreads throughout the body, affecting many, including distant cells.

"World science has already had evidence that the Kloto gene can suppress the viability of glioblastoma cells. The uniqueness of our research is that they were carried out precisely on the secreted form of the Clotho protein. This methodological nuance allows us to take a slightly broader look at the mechanisms of development of tumor diseases," says Vsevolod Melekhin, head of the research group, associate professor at the Ural Federal University, an employee of the Ural State Medical University and the Institute of Medical Cell Technologies.

In their experiments, Yekaterinburg scientists used the Kloto gene embedded in a plasmid — a closed ring DNA molecule taken from bacteria. Together with her, the gene was implanted into glioblastoma cells. The plasmid cannot penetrate the cell on its own, for this the researchers used a complex of positively charged DNA lipids: they are readily attracted to the negatively charged surface of the cell, merge with the cell membrane, which also mainly consists of lipids, and pass through it into the cell.

"It is easier to deliver a gene using viral constructs that easily penetrate the cell. But viruses have the ability to integrate into the genome — the totality of the hereditary material of the cell. And the use of technologies related to interference in the genome is limited by legislation and ethical standards. The plasmid acts inside the cell for only two to three weeks, and then it is destroyed, leaving no trace in the cell genome," explains Vsevolod Melekhin.

Placed inside glioblastoma cells and in a state of hyperactivity, the Kloto gene produced a secreted protein of the same name, which entered the intercellular space. After conducting three tests, the scientists recorded that after 72 hours, protein production increased by almost 15 times, the viability of glioblastoma cells fell by 8%, the number of cells decreased by almost 20% of the control values.

"The body gets rid of unnecessary or damaged, mutated cells with the help of apoptosis — a mechanism that triggers a program of self-destruction, "suicide" of cells. In the cells of malignant tumors, the mechanism of apoptosis is blocked, so they multiply constantly and unrestrainedly. However, as a result of our experiment, we registered a significant increase in the number of apoptotic cells," Melekhin adds.

According to the scientist, the research conducted on the secreted form of the Clotho protein is another step towards creating more effective therapeutic and diagnostic approaches.

Reference

The Kloto gene was discovered in 1997. Science has established that this gene has an effect on the aging processes of the body: the less active the gene, the more distinct the signs of premature aging, and on the contrary, the higher the expression of the gene, the longer the lifespan of the organism. The relationships of the Kloto gene behavior with diseases such as hypertension, diabetes mellitus, pulmonary emphysema, and other pathological age-related changes have been traced. In the mid-2000s, studies began on the effect of the Kloto gene on the development of oncological diseases — lung, breast, liver cancer. However, there is still insufficient information about the mechanisms of antitumor effects of the activity of the Kloto gene.

Ural Federal University (UrFU) is one of the leading universities in Russia with a century—old history, one of the leaders of the Priority 2030 program, No. 1 in the country in terms of admission volumes. It is located in Yekaterinburg, the capital of the 2023 World Summer Student Games, the winning city of the Russian Government's selection for the creation of university campuses. The university performs the functions of the project office of the Ural Interregional World-class Scientific and Educational Center (REC).

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