Exposure to radiation can wreak havoc on cells, tissue and organs. However, some tissues are more vulnerable to radiation damage than others. Scientists have known these differences involved the well-studied tumour-suppressor protein, p53, which initiates a cell’s auto-destruct programs.
But, levels of this protein are often similar in tissues with vastly different sensitivities to radiation. So how exactly is p53 involved? A new study published in Nature sheds some light on this mystery.
A Dynamic Process
The team looked at tissues in mice which have different sensitivities to radiation therapy yet are known to express similar levels of p53. For example, the spleen and thymus, which are highly vulnerable and the large and small intestines, which are more radioresistant.
The researchers found that cellular survival after radiation exposure depends on the behaviour of p53 over time. In vulnerable tissues, its levels go up and remain high, leading to cell death. Whereas, in tissues that tend to survive radiation damage, its levels oscillate up and down. In the intestines, quantitative imaging analyses showed that p53 levels peaked and then declined a few hours after irradiation. In comparison, levels remained high over the same time period in the spleen and the thymus.
Previous research was limited by only viewing these processes as snapshots. By watching how things change temporally, the researchers were able to gain much richer information crucial for dissecting disease and producing new therapies.
p53: Radiation Vulnerability
Notably, the team found that tumours in mice were more vulnerable to radiation after being given a drug which blocks p53 levels from declining. Irradiation causes p53 levels to increase, but in some cases the protein MDM2 degrades p53, bringing the levels backdown and enabling cell survival. By using a drug that blocks MDM2 activity, the researchers were able to ensure p53 levels remain elevated in cells where it would otherwise decline.
Tumours treated in this way shrunk significantly more than when receiving irradiation or MDM2-inhibition alone. In the intestine, which is normally more resistant to radiation, the addition of this drug reduced cell viability and survival. These findings suggest that new combination therapies for cancer may yield better outcomes.
p53: Preventing Resistance
Additionally, some cancers can become resistant to radiation therapy. Therefore, the team explored whether manipulating p53 dynamics could increase tumour vulnerability. In mice with transplanted human colon cancer tumours, the team observed significant tumour shrinkage following this irradiation-drug combination therapy. After 6 weeks, these tumours were five-times smaller than those treated with the drug alone, and half the size of those treated with only radiation.
While further studies will be needed to understand p53 dynamics in different tissues, understanding how it behaves over time is a critical piece of the puzzle. This study brings us one step closer to developing better and more efficient therapies.
