How do cancer cells die? 

In order to hijack a tumor cell into killing itself, cancer therapies are designed to damage DNA. DNA damage turns on programmed cell death, a pathway termed apoptosis, which results in the tumor dying. This cell death pathway is controlled by a protein coined the “guardian of the genome” – tumor protein 53 (p53). By sensing and responding to the DNA damage caused by these therapies, p53 helps build and turn on cell death machinery. However, when p53 is mutated, p53 cannot function normally, causing unhealthy, damaged cells to continue growing instead of killing themselves off for the better of the organism. This unchecked cell growth leads to cancer. It’s no surprise then that p53 is the most commonly mutated gene across all cancer types.

Researchers based in the Netherlands had some questions about the use of cancer therapies that cause DNA damage and apoptosis. If p53, the protein that triggers cell death, doesn’t work in cancer cells anymore, how are cancer therapies able to cause cell apoptosis and kill tumors? These researchers, correctly, believed that another signal must exist to turn on apoptosis.

Together with researchers in Denmark, this team identified a totally novel mechanism to turn on cell death. By treating tumor samples from p53-deficient cancers with DNA-damaging chemicals, researchers saw that apoptosis still occurred but was simply triggered by a different protein. It turns out that when p53 is mutated, apoptosis gets turned on by the protein Schlafen family member 11 (SLFN11). Interestingly, SLFN11 has been recognized as one of the strongest biomarkers for cancer treatment success. Meaning, if SLFN11 is functional, even cells deficient in p53 can undergo cell death, consequently shrinking the tumor. 

The identification of SLFN11 represents a landmark in cancer research, potentially opening up new avenues of therapy development. This work finally explains the current application of DNA-damaging therapies to cancer patients who often have a mutated p53, reminding scientists to keep asking the seemingly basic questions.

This study was led by Nicolaas J. Boon at Oncode Institute, Utrecht, Netherlands with corresponding authors Reuven Agami and Thijn R. Brummelkamp.

Corresponding Author: Nina C. Benites

Press Article: Researchers discover new pathway to cancer cell suicide (ScienceDaily)

Research Article: DNA damage induces p53-independent apoptosis through ribosome stalling (Science)

Image Credit: WikiMedia

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