The factors that lead to the formation of defective cells and which can cause cancer are diverse and, even after years of research in this area, not yet fully understood.
This is because some cancers are hereditary, while others can be linked to environmental factors. There is also the occurrence of tumors due to independent mutations in individuals that are not hereditary.
Now researchers at the UFRJ (Federal University of Rio de Janeiro) have just identified one of these mechanisms, which occurs in the formation of p53 protein aggregates known as the “guardians of the genome”. It is responsible for numerous vital functions in the body, such as controlling the cell cycle and fighting tumor cells, and is located in the nucleus of somatic (non-sexual) cells in our body.
The result is the result of years of basic research at the INCT (National Institute of Science and Technology) and at Inbeb (National Center for Structural Biology and Bioimaging), at the UFRJ, coordinated by a doctor and professor at the Leopoldo de Meis Institute of Medical Biochemistry, Jerson Lima Silva.
The article describing the phenomenon was the cover of the latest edition of the Royal Society of Chemistry’s (United Kingdom) Chemical Science journal, a reference in the field of chemical research applied to biology and medicine.
Because it is located in the nucleus, more precisely in small structures in the nucleus called nucleoli (small membraneless vesicles with a high concentration of nucleic acid, the substance that makes DNA and RNA molecules), p53 acts directly when reading a part DNA and gene regulation. Its lifespan is short and is only expressed when there is a need to take action.
But the p53 mutants accumulate in the cell nucleus, can no longer exercise their protective function and, worse still: They can still “connect” to other proteins that have a tumor-suppressing effect, which leads to the so-called gain in metastatic function.
Aggregates arise according to the phase separation behavior of the substances in the core, from the liquid (soluble) state to the gel form to the solid. This chain of events is associated with the development or regression of malignant tumors.
Science has known for years that aggregates of this protein are present in large quantities in breast tumor biopsies, for example. However, contrary to previous research, Brazilian scientists have focused on aspects at the molecular level of the protein.
“This protein was considered to be oncogenic [causadora de câncer] in the 1980s. There was a popular notion that it was an “untreatable” protein, so it hasn’t received much attention since then, “says Silva.
In his laboratory, the studies on the molecular structures and biochemical properties of the cell nucleus began with the question: “Isn’t there the aggregation of p53 during this transition from the liquid state, which ultimately forms a firmer gel?” He explains.
This first hypothesis was formulated from the observation of other conditions that are also related to the formation of cell aggregates, such as Alzheimer’s, Parkinson’s, myotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. With them, the phase separation played an important role in the function of the proteins involved.
From refined techniques of transmission electron microscopy, nuclear magnetic resonance spectroscopy (a technique that studies the physical or chemical properties of atomic nuclei), and fluorescence microscopy (fluorescent staining of the normal p53 protein and mutated form to see how it organizes itself) at its core), the scientists were able to analyze every step in the sequence of events involved in the formation of the anomaly.
“We focused on understanding why it converges on these aggregation pathways, something that has already been linked to cancer and is even more common in more aggressive forms of the disease,” explains physiotherapist Murilo Pedrote, co-author of the article .
Pedrote and chemist Elaine Petronilho shared the “hard work” of research in their postdoc projects in Silva’s laboratory.
“By identifying this phase separation process before aggregates form, we have a potential target for therapies,” he explains.
Finding a possible cancer treatment is one of the relevant issues, but not the only one. With knowledge of the mechanisms by which tumors develop, it is also possible to develop highly specialized diagnostic tests that contribute to the early detection of the cancer focus.
“In Alzheimer’s disease, there are imaging methods that can make protein aggregates visible, which are toxic and lead to the death of nerve cells. For cancer, we can develop a technique similar to that of a PET scan [tomografia computadorizada pós emissão, na sigla em inglês]“, Says Silva.
Despite its value for applied science, the focus of research has been on basic research, which is fundamental to generating the knowledge base for technological development. Countries that have achieved scientific and technological sovereignty have done so by continually investing in this type of science.
Brazil, on the other hand, goes against the most important technological powers in the world such as the USA, Israel and China. In recent years the country has experienced sharp cuts in scientific and technological development, most recently in the National Fund for Scientific and Technological Development (FNDCT).
Also in the implementation of national programs to promote science, such as in the context of the INCTs, which are directly funded by the Ministry of Science, Technology and Information (MCTI) and the CNPq (National Council for Scientific and Technological Development), linked to In der Mappe the continuity of scientific research depends on the approval and availability of funding for research grants – postgraduate grants – in the country.
During his postgraduate studies and most of his undergraduate studies, Pedrote received a Faperj grant for his research. During her postdoc time, the scientist received a tenth grade in the evaluation of the scientific project and thus a higher remuneration for research assistants.
“Still, there are of course concerns. I would like to go abroad, gain experience abroad and also because the political situation in Brazil is not favorable today, ”he says.
Although there were no cuts in Faperj, during the pandemic the agency continued to only fund ongoing grants and research grants without opening public notices for infrastructure projects.
“Sometimes we have the equipment, we get approval for the research project, but the budget is paralyzed. When he returns, the price of the dollar will have gone up two, three times, and then the project we wanted to do with $ 1 million will be three times as valuable. The higher the level of excellence, the more difficult it is to make progress in research, ”says Silva.