Cell survival after radiation exposure depends on the specific behavior of proteins

Exposure to radiation can wreak indiscriminate damage to cells, tissues and organs. Oddly, however, some tissues are more vulnerable to radiation damage than others.

Scientists know that these differences involve the protein p53, a well-studied tumor suppressor protein that initiates a cell’s self-destruction programs. Yet the levels of this sentinel protein are often similar in tissues with very different sensitivities to radiation, which begs the question: how is p53 involved?

A new study by researchers at the Blavatnik Institute at Harvard Medical School, Massachusetts General Hospital and the Novartis Institutes for BioMedical Research is now shedding light on this mystery.

Reporting in Nature communications on February 9, they describe how cell survival after radiation exposure depends on the behavior of p53 over time. In invulnerable tissue, p53 levels increase and remain elevated, resulting in cell death. In tissues that tend to survive radiation damage, p53 levels fluctuate up and down.

“Dynamics are important. How things change over time matters,” said co-correspondent author Galit Lahav, Novartis Professor of Systems Biology at HMS. “Our ability to understand biology is limited when we only watch snapshots. Seeing how things move over time, we gain much richer information that can be essential in dissecting disease and creating new therapies.”

In particular, the results suggest new strategies to improve combination therapies against cancer. The team found that certain types of tumors in mice were more vulnerable to radiation after being given a drug that prevents p53 levels from dropping and fluctuating. Tumors treated in this way shrink much more than when given alone or with the drug alone.

“We were able to relate the differences in temporal expression of p53 to the response to radiation, and this information allowed us to ‘coax’ the radioresistant tumors into more radiosensitive tumors,” said co-corresponding author Ralph Weissleder, the Thrall family professor of radiology and professor of HMS. systems biology at Mass General. “This is an incredibly exciting study showing that basic science done in rigorous quantitative fashion can lead to important new clinical discoveries.”

When cells are exposed to ionizing radiation, high-energy atomic particles randomly attack the delicate molecular machinery inside. If this damage cannot be repaired, especially to DNA, the cells will self-destruct to protect the surrounding tissue and organism as a whole.

This act of cellular seppuku is regulated by p53, which acts as a sentinel for genomic damage. The protein is also a famous tumor suppressor – about half of human cancers have p53 mutations that make it defective or suboptimal. Previously, Lahav and his colleagues revealed the dynamic behavior of p53 over time and how it affects the effectiveness of anticancer drugs, the fate of cells, etc.

Stronger together

In the current study, Lahav, Weissleder and their team looked at tissues in mice that have very different sensitivities to ionizing radiation but are known to express comparable levels of p53 – the spleen and thymus, which are very vulnerable, and the large and small intestines, which are more radiation resistant.

Under normal conditions, cells express little or no p53. After radiation exposure, all four tissues expressed elevated p53 as well as other markers of DNA and cell damage as expected. But quantitative imaging scans revealed that p53 in the intestines peaked and then declined within hours of irradiation. In contrast, p53 in the spleen and thymus remained elevated during the same period.

To probe the behavioral effects of p53, the team used an experimental cancer drug to inhibit MDM2, a protein that degrades p53. They found that by blocking MDM2 activity after radiation exposure, p53 could be forced to stay high in cells where it would otherwise decline. In the intestine, which is normally more resistant to radiation, adding the drug reduced cell viability and survival.

Some cancers can become resistant to radiation therapy. Thus, the team explored whether manipulation of p53 dynamics could increase tumor vulnerability, focusing on human colon cancer cell lines with functional, non-mutated p53.

In mice with transplanted human colon cancer tumors, the team observed significant tumor shrinkage after a single dose of MDM2 inhibitor given shortly after irradiation. After about 6 weeks, the tumors treated with radiation and the drug together were five times smaller than those treated with the drug alone and half of those treated with radiation alone.

By irradiating first, we force cancer cells to activate p53, and by adding an MDM2 inhibitor on top of that, we can keep p53 active for longer. This combination has a much stronger effect than either alone. “

Galit Lahav, co-author, Novartis Professor of Systems Biology, Harvard Medical School

The results support the importance of understanding the dynamics of p53 and how to manipulate it to treat cancer.

Combination therapies using MDM2 inhibitors are currently being evaluated in clinical trials, the authors note, but these efforts are not designed to examine the underlying mechanisms and timing of treatments. Further studies are needed to better understand the dynamics of p53 in cancer, which may shed light on how to best combine and time therapies to treat cancer patients.

Furthermore, although researchers have identified differences in the dynamics of p53 in different tissues after radiation exposure, the biological pathways that lead to these differences remain a question for future study.

“For a laboratory studying p53, cancer is still a major motivation. Our goal is to gain knowledge to help develop better and more effective therapies, ”said Lahav. “Understanding how p53 behaves over time under different conditions is a critical piece of the puzzle.”