Study Discovers Natural Protective Mechanism in Cancer Cells

Researchers at the University of Bayreuth have discovered a natural protective mechanism that leads to the programmed death of potentially diseased cells, which protects cells from cancer that can develop as a result of irregular distribution of genetic information to daughter cells.

Published in Nature, the study followed up on a contribution to the regulation of separase. The strict regulation of this enzyme during cell division is normally a prerequisite for healthy daughter cells to develop. However, if the separase is activated too early, there is a risk of cellular transformation into malignant cancer cells, according to the study.

In this follow-up study, the researchers have discovered a previously unknown protective mechanism of the cell. It is separase itself that prevents the threatening consequences of its premature activity by inducing the dividing cell to undergo apoptosis. This happens because the separase repurposes 2 proteins that usually have the task of counteracting apoptosis, according to the study. These are the proteins, MCL1 and BCL-XL.

In a healthy cell, MCL1 and BCL-XL prevent the protein BAK from causing the cell to die. Yet, when separase becomes active too early, it cuts these 2 proteins, the researchers wrote. As a result, they can no longer fulfill their cell protecting function and BAK is free to induce apoptosis. Moreover, separase-dependent processing transforms MCL1 and BCL-XL from anti-apoptotic factors into pro-apoptotic protein fragments.

Based on these findings, the researchers discovered another important mechanism in the process of cell division. It ensures that the separase spares healthy cells and actually only attacks the proteins MCL1 and BCL-XL in the case of an imminent pathological cell development.

The separase is prepared for this attack as soon as the 2 proteins have been modified by phosphate groups. The enzyme NEK2A is responsible the phosphorylation of the proteins. Therefore, NEK2A is degraded relatively early in the course of cell development. Before the cell begins to divide, the enzyme has disappeared, provided that the spindle assembly checkpoint is functional and can ensure that cell division proceeds in orderly manner.

In this case, the separase fulfils its functions at the right time without being able to identify and attack the no longer phosphorylated MCL1 and BCL-XL. However, if the spindle assembly checkpoint is defective, the process of cell division is accelerated. Although NEK2A is still present in the cell, the separase becomes active and once it recognizes the 2 proteins, apoptosis is initiated immediately, according to the study.

The process is referred to by the researchers as “minimal duration of early mitosis checkpoint.” It is an emergency mechanism that comes into effect as soon as a defective spindle assembly checkpoint causes chromosome mis-segregation associated with the risk of carcinogenesis, according to the study.

The findings offer several starting points for new cancer therapies as well as more information MCL1 and BCL-XL, the study noted. According to the researchers, a promising approach in the fight against cancer could now be to encourage separase-dependent transformation of MCL1 and BCL-XL into pro-apoptotic factors. This would be especially harmful to diseased cells, the authors concluded.

Reference

• Programmed cell death: Bayreuth geneticists discover cellular mechanism protecting against cancer. University Bayreuth. Published April 23, 2020. https://www.uni-bayreuth.de/en/university/press/press-releases/2020/059-cell-death/index.html. Accessed April 28, 2020.