New knowledge about cell division may improve cancer treatment

Therapy Breakthroughs 15. may 2021 3 min CARD Deputy Director and Professor Francesco Cecconi Written by Kristian Sjøgren

Researchers in Denmark have identified a protein that regulates the rate of cell division. This discovery provides insight that may be used to improve the treatment of people with cancer.

Cell division is a very precisely choreographed dance in which thousands of molecules, proteins and fragments of DNA must interact to make one cell become two.

Cell division is the bedrock of life, but it can also take life, such as when the cell division does not copy the genome correctly or goes haywire. Both can lead to cancer.

A new study from Denmark now provides novel insight into how cell division takes place and what can go wrong.

“We found that a specific protein is extremely important in controlling the rate at which the cell cycle progresses. If the levels of this protein are too low, the cell divides too fast, increasing the risk of damaging the genome, with the associated risk of developing cancer. But if we can attack the cells’ repair mechanisms, we might be able to use these as a means to get cancer cells to self-destruct,” explains an author behind the study, Francesco Cecconi, Professor, Danish Cancer Society, Copenhagen.

The research, which was carried out in collaboration with Jiri Bartek, Professor, Danish Cancer Society and others, has been published in Nature.

Protein has a previously unknown role in regulating cell division

Cyclin D and Ambra1 are proteins central to the new discovery, with cyclin D known for many years as being important for cell division.

During the cell cycle, the levels of cyclin D oscillate. Cell division accelerates as the level of cyclin D increases because it assists in copying the genome. Conversely, declining levels of cyclin D stop cell division.

However, the role of Ambra1 in cell division was not known previously until the researchers mapped this, showing that increasing levels of Ambra1 reduce the levels of cyclin D and vice versa.

“In the issue of Nature, three research groups arrived at the same result but approached the problem differently. This shows that the results are very solid and that Ambra1 definitely plays this role,” says Francesco Cecconi.

Cell division in overdrive

The interesting thing about the research is not only identifying a previously unknown regulator of cyclin D and cell division but also how this affects the carefully choreographed cell division, which can get out of control.

For example, if the levels of Ambra1 fall excessively, this is like taking one foot off the brake for cyclin D, which causes the cells to copy their genome at a furious tempo.

The faster the cells copy the genome, the greater the risk of errors, and too many defects accumulating in the genome can lead to the development of cancer.

“Excessive quantities of cyclin D because of gene amplification are already associated with an increased risk of metastasis in such diseases as cancer of the lung, bladder and breast,” explains Francesco Cecconi.

Excessive genetic damage causes cells to self-destruct

However, excessive damage to the genome might also result in even cancer cells not functioning.

If this happens, the cells self-destruct (apoptosis) instead of repairing what can no longer be fixed.

For the cancer cells, a little damage to the genome is good, but more is too much, and researchers may be able to exploit this therapeutically.

“A cancer cell, for example, uses cell mechanisms to keep repairing the genome, but blocking this repair mechanism may accumulate so much damage to the genome in the cancer cells that apoptosis is inevitable,” says Francesco Cecconi.

Medicine can cause apoptosis of cancer cells

The researchers tested whether Ambra1 could be a promising target for novel cancer treatments.

In experiments with samples from humans and mice, the researchers showed that stopping the repair mechanisms results in excessive cyclin D levels in cancer cells. This is associated with accumulation of damage to the genome, resulting in apoptosis.

In one of the other articles published in the issue of Nature, researchers from the United States show that Ambra1 plays a role in developing chemotherapy-resistant cancer, and overall, the three articles indicate the important role Ambra1 has in cell division, the development of cancer and novel treatment options.

“The idea is that people with cancer will also have their levels of Ambra1 and cyclin D determined. If this signalling pathway is part of the tumour’s functioning mechanism, we can use it to eliminate the tumour cells’ ability to repair the genome. If we can limit the repair, we can also kill the tumour cells. Another option is to inhibit the effect of excessive cyclin D and thereby make the cancer cells more sensitive to other treatments,” concludes Francesco Cecconi.

The researchers have already studied these possibilities in tumour cells, but they have found no evidence yet that it will work for humans. However, they will investigate this in the future.

Ambra1 regulates cyclin D2 to guard S-phase entry and genomic integrity” has been published in Nature. In 2016, the Novo Nordisk Foundation awarded a grant to Francesco Cecconi for the project The Autophagy Regulator Ambra1 and Lung Cancer: a Novel Prognostic Biomarker and Therapeutic Target. In 2020, the article's co-author Jiri Bartek, Danish Cancer Society received funding from the Novo Nordisk Foundation for the project "Replication stress: Mechanisms and roles in human health and disease".

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