How p53 Decides between Cell Cycle Arrest or Apoptosis

There is an ongoing battle between cancer cells and p53, the protein known as “the guardian of the genome.” In a study published today in Cell Reports, University of Trento researchers identified a number of factors that influence the outcome of this battle—and, therefore, the effectiveness of cancer treatments.

The p53 protein can cause either of two scenarios: first, it can stop cancer cells from proliferating, and second, it can increase their death rate. However, it has not been understood what elements lead to which outcome. But in the new study, researchers found a specific factor—a protein known as DHX30—that determines the way in which p53 handles cancer cells.

“When cancer cells are treated with a certain drug, it is the action of this switch (DHX30) that makes them to go towards cell death and not in the direction of cell cycle arrest,” says coauthor Erik Dassi.

The “certain drug” that the researchers used for this study was the small molecule Nutlin, which acts as a p53 activator. “The drug activates p53, the well-known guardian of the genome, which oversees the various pathways of cancer cells,” says senior author Albert Inga.

According to Inga, the thought for decades has been that p53 could be made to stimulate apoptosis by intervening upstream of the p53 gene. However, the University of Trento team now believes that a significant part of this decision is made downstream of p53 rather than upstream.

“In other words, the activation of p53 in cancer cells can lead to a number of possible responses in the cells; the ‘switch’ that we identified regulates the response that could be the most important for therapeutic reasons,” says first author Dario Rizzotto. “When there is no interaction between DHX30 and relevant mRNAs, cancer cells die.”

This is an important discovery to develop more tailored and effective molecular treatments, especially to treat certain types of tumors—for example, solid tumors in the colon, breast, and lung.

Image: The graphical abstract illustrates the main findings of the study of the cell death processes in cancer cells. Image courtesy of Alberto Inga, UniTrento.