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Researchers discover new pathway to cancer cell suicide

Researchers discover new pathway to cancer cell suicide


Chemotherapy kills cancer cells. However, the mechanism by which these cells die appears to be different from what was previously understood. Researchers at the Netherlands Cancer Research Institute, led by Tine Blumerkamp, ​​have discovered an entirely new way in which cancer cells die: via the Schlafen-11 gene. “This is a very unexpected finding. Cancer patients have been treated with chemotherapy for almost a century, but this pathway to cell death has never been observed before. When this occurs requires further investigation. This finding could ultimately have implications for the treatment of cancer patients. ” They present their findings as follows: science.

Many cancer treatments damage the DNA of cells. If the damage is too great to repair, cells can begin to die on their own. In high school biology, we are taught that the protein p53 is responsible for this process. p53 ensures the repair of damaged DNA, but when the damage becomes too severe it initiates cell suicide. This prevents uncontrolled cell division and cancer formation.

Surprise: Unanswered Questions

Although this sounds like a foolproof system, the reality is more complex. “In more than half of tumors, p53 is no longer functional,” says Thijn Brummelkamp. “P53, which plays an important role, plays no role here. So, why do cancer cells that do not have p53 die even if their DNA is damaged by chemotherapy or radiation? I was surprised. In fact, it turned out to be an unanswered question.”

His research group, together with colleague Reuven Agami's group, then discovered a previously unknown way in which cells die after DNA damage. In the lab, they treated the cells with chemotherapy and carefully altered their DNA. Thijn: “We were looking for genetic changes that would make cells more resistant to chemotherapy. Our group has a lot of experience in selectively disabling genes, and we're bringing that here. Perfectly applicable.”*

A new key to cell death

A research group has discovered a new pathway to cell death led by the gene Schlafen11 (SLFN11) by switching off the gene. Lead researcher Nicholas Boone: “When DNA damage occurs, SLFN11 shuts down the cell's protein factories, the ribosomes. This creates tremendous stress on these cells, leading to cell death. The new pathway completely bypasses p53.

The SLFN11 gene is well known in cancer research. It is often inactive in patients' tumors that do not respond to chemotherapy, Thijn says. “We can now explain this association. When cells lack SLFN11, they don't die like this in response to DNA damage. The cells survive, and the cancer persists.”

Impact on cancer treatment

“This discovery, as usual in basic research, opens up many new research questions,” says Thijn. “Although we have demonstrated our findings in cancer cells grown in the lab, many important questions remain: When and where does this pathway occur in patients? How does it affect immunotherapy and chemotherapy? Does it affect the side effects of cancer treatment? In this form, the rate of cell death has also been shown to play an important role in patients, and this discovery These are important questions to investigate further.”

*Turning off genes one by one

Humans have thousands of genes, many of which have functions unknown to us. To elucidate the role of genes, researcher Thijn Brummelkamp developed a method using haploid cells. These cells contain only one copy of each gene, while normal cells in our body contain two copies. In genetic experiments he can have difficulty working with two copies, since often changes (mutations) occur in only one of them. This makes it difficult to observe the effects of these mutations.

Dr. Blumelkamp, ​​along with other researchers, has been using this versatile method to elucidate processes important in disease for many years. For example, his group recently discovered that cells can produce lipids in a different way than previously known. They revealed how certain viruses, including the deadly Ebola virus, enter human cells. They took a closer look at cancer cells' resistance to certain treatments and identified proteins that act as brakes on the immune system that are relevant to cancer immunotherapy. In recent years, his team discovered two enzymes that had gone undiscovered for 40 years, and they turned out to be essential for muscle function and brain development.

This study was funded by KWF Dutch Cancer Society, Oncode Institute, and Health Holland.




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