Cell survival after radiation exposure depends on the behavior of a particular protein

If you are exposed to radiation, they can damage cells, cigarettes and organs. Ironically, however, some tissues are more vulnerable to radiation damage than others.

Scientists know that these differences include p53 protein, a well-studied tumor suppressor protein that initiates cell self-destruction programs. However, levels of this sentinel protein are often similar in interweaving with a very different sensitivity to radiation, raising 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 now sheds light on this mystery.

Reporting Nature Communication on Feb. 9, they report how cell survival after radiation exposure is dependent on p53 transport over time. Inaccessible figs, p53 levels go up and stay high, leading to cell death. In interfacing that tends to survive radiation damage, p53 levels oscillate up and down.

“Dynamics are important. How things change over time is important,” said the corresponding author Galit Lahav, Novartis Professor of Systems Biology at HMS. “Our ability to understand biology is limited when we only look at small pictures. By seeing how things grow over time, we get much richer information that could potentially be essential for the spread of disease and the creation of new cures.

In particular, the findings suggest new strategies to develop combination therapies for cancer. The team found that certain types of tumors in mice were more vulnerable to radiation after they were given a drug that blocks p53 levels from shrinking and oscillating. Tumors treated this way shrunk significantly more than when given either radiation alone or the drug alone.

“We were able to link differences in p53 temporal expression with radiation response, and these insights allowed radioresistant tumors to‘ coax ’into more radiosensitive ones,” said co-author Ralph Weissleder , Thrall Family Professor of Radiation and HMS professor of systems biology at Mass General. “This is a very interesting study that shows that basic science conducted in hard quantitative fashion can lead to important new clinical discoveries.”

When cells are exposed to ionizing radiation, high-energy atomic particles haphazardly attack the delicate molecular devices in the interior. If this damage cannot be repaired, especially on DNA, cells destroy themselves to protect the surrounding material and organism.

This action of cellular seppuku is regulated by p53, which acts as a sentinel for genomic damage. The protein is also a well-known tumor suppressor – about half of human cancers have p53 mutations that make it deficient or suboptimal. Previously, Lahav and colleagues demonstrated the dynamic behavior of p53 over time and how it affects the effectiveness of cancer drugs, cell violence, and more.

Stronger together

In the current study, Lahav, Weissleder, and their team looked at figs in mice that have a very different sensitivity to ionizing radiation but are known to express relative levels of p53 – the spleen and thymus, which is very vulnerable, and the large and small intestines, which are more radioactive.

Under normal conditions, cells express very little without p53. Following radiation exposure, the four tissues expressed elevated p53 along with other traces of DNA and cell damage as expected. But quantitative image analyzes showed that p53 in the intestines peaked and then declined a few hours after irradiation. In contrast, p53 remained high in the spleen and thymus over the same period.

To investigate the behavioral effects of p53, the team used an anti – cancer experimental drug to inhibit MDM2, a p53 – reducing protein. They found that, by inhibiting MDM2 activity after radiation exposure, p53 could be increased in cells where it would degrade. In the abdomen, which is usually more resistant to radiation, the addition of the drug reduced the viability and survival of cells.

Some cancers may be resistant to radiation therapy. Therefore, the team investigated whether the treatment of p53 dynamics could increase tumor vulnerability, focusing on human colon cancer cell lines with undeveloped, active p53.

In mice with transplanted human colon cancer tumors, the team observed major tumor reduction after a single dose of MDM2 inhibitor administered shortly after irradiation. After about 6 weeks, tumors treated with radiation and the drug combined were five times smaller than those treated with the drug alone and half the size of those treated with direct radiation.

By irradiating first, we cause the p53 cancer cells to activate, and by adding an MDM2 inhibitor in addition, we can keep p53 active longer. This combination has a much stronger effect than either alone. “

Galit Lahav, Corresponding Author, Novartis Professor of Systems Biology, Harvard Medical School

The findings support the importance of understanding the dynamics of p53 and how to treat 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 investigate the basic mechanisms and timing of treatments. Further studies are needed to better understand the dynamics of p53 in cancer, which will provide information on how they can better mix and time up patients with cancer.

Furthermore, although the researchers identified differences in p53 dinamics in different figs after radiation exposure, the biological pathways leading to these differences remain. question for future study.

“For a laboratory that studies p53, cancer is always a key motivator. Our goal is to gain experience to help develop better and more effective treatments,” Lahav said. “Understanding how p53 behaves over time in different situations is a crucial piece of the puzzle.”