Why do elephants barely get cancer?

Elephant genes provide new clues as to why these animals rarely have cancer. Knowing this could help prevent many cases of cancer in humans.

The p53 protein, when working properly, protects against cancer. An international study with the participation of the Institute of Biotechnology and Biomedicine (IBB) of the Autonomous University of Barcelona (UAB) has identified how the 20 different forms of the p53 protein that are exclusive to elephants are activated in elephants. This activation increases the sensitivity of detection and the efficiency of the subsequent reaction against carcinogenic conditions.

The work represents a significant advance in understanding how p53 contributes to preventing the development of cancer. What was discovered in this research provides a new perspective for the study of the activation of this protein in humans, in which it only occurs in one form, and the investigation of targeted pharmacological therapies.

Scientists from seven institutions have used pioneering bioinformatics modeling to investigate the molecular interactions of the p53 protein. The work has been coordinated by Konstantinos Karakostis, currently a Maria Zambrano researcher in the Functional and Comparative Genomics group at the IBB.

Cells routinely replicate, producing new cells to replace old ones, and each new cell contains new copies of the DNA. These new cells should be exact copies of the old ones, but mutations occur if errors are generated. Most errors are immediately repaired by the cell, although the number of mutations and the quality of the repairs are affected by both genetic and external circumstances. Toxic compounds, stress, poor living conditions, and aging can increase the rate of mutation.

The risk of tumors resulting from the accumulation of these genetic mutations increases with age, but unlike humans, elephants seem to resist this tendency. Despite their large size and life expectancy comparable to that of humans, cancer mortality in elephants is estimated to be less than 5% (while in humans it is estimated to be as high as 25%). Scientists link elephants’ high resistance to cancer to their 20 copies of the p53 gene, which they call the ‘guardian of the genome’, compared to the single p53 gene found in other mammals.

“This very complex and interesting study shows that elephants are much more than animals of impressive size and that it is important not only to conserve these characteristic animals, but also to study them in detail. After all, their genetics and physiology are conditioned by evolutionary history as well as current ecology, diet and behaviour,” says Fritz Vollrath of the University of Oxford and member of the Save the Elephants.

An elephant in East Africa. (Photo: USGS)

The P53 protein plays a key role in the regulation of DNA repair mechanisms and suppresses uncontrolled cell growth. This protein is activated when DNA is damaged and helps orchestrate a response that stops DNA replication and repairs uncorrected copies in the cell. In replicated cells with undamaged DNA, p53 repair activity is unnecessary and is inactivated by another protein, MDM2 E3 ubiquitin ligase.

The regulated interaction between p53 and MDM2 is essential for healthy cells to divide and replicate, damaged cells to repair themselves, and cells with failed repairs or extensive damage to be destroyed.

The elephant may seem genetically gifted with 40 alleles, or versions, of its twenty p53 genes, but each of these alleles is structurally slightly different, giving this animal a much broader range of anticancer molecular interactions than a human , with only two alleles of a single gene.

Using biochemical analyzes and computer simulations, researchers have uncovered key differences in the regulated interaction between the various elephant p53 isoforms and MDM2.

Small variations in molecular sequence give rise to a different molecular structure for each of the p53 molecules. Small structural differences alter the three-dimensional shape of the isoform and significantly modify the function of the interaction between p53 and MDM2.

The research team found that, as a result of changes in coding sequences and molecular structure, several p53s escape interaction with MDM2, which would normally result in their inactivation. The findings are the first to show that the different p53 isoforms found in the elephant are not degraded or inactivated by MDM2, unlike in humans.

“This is an exciting advance in our understanding of how p53 helps prevent cancer development. In humans, the same p53 protein is responsible for deciding whether cells should stop proliferating or enter apoptosis, but how it makes this decision has been difficult to understand. The existence of several isoforms of p53 in elephants, with different capacities to interact with MDM2, offers an innovative and interesting approach to provide new and revealing information on the tumor suppressor activity of p53″, explains Robin Fåhraeus, from INSERM in Paris, study co-author.

Better understanding how p53 molecules are activated and when this may lead to increased sensitivity and response against carcinogenic conditions is an important perspective for research on p53 activation and targeted drug therapies in humans.

“Conceptually, the accumulation of structurally modified p53 groups, which collectively or synergistically regulate responses to various stresses in the cell, establishes an alternative mechanistic model of cell regulation of great importance and potential for biomedical applications”, concludes Konstantinos Karakostis, researcher from the IBB and lead author of the study.

Scientists from the universities of Gdansk and Edinburgh, and the MMCI (Masaryk Memorial Cancer Institute) have also participated in the study.

The study is titled “The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer, and has been published in the academic journal Molecular Biology and Evolution. (Source: UAB. CC BY-NC 4.0)