Cancer cells break their own DNA to defend themselves against radiation
RIrradiation inflicts considerable damage to the DNA of cells. For many cells, the damage is too complex to repair and the cells die, making radiation therapy a first-line treatment for cancer. However, some tumor cells are resistant to radiation: they repair the damage inflicted and survive. A new study, published today in Sciencefinds that tumor cells buy time for these repairs by self-inflicting smaller, more easily repairable damage to their DNA, thereby expanding the window in which they can repair larger radiation damage.
The study “presents an intriguing and essentially unanticipated finding that tumor cells have the ability to promote a ‘secondary wave of strand breaks’ in response to stress such as ionizing radiation,” said David Gewirtz, a pharmacologist at the Virginia Commonwealth University, which was not involved in the study, says The scientist in an email. Members of his own lab had also observed such breaks, he wrote, but were unable to determine their origin. “The authors identify the ‘culprit’ as caspase-activated DNAse (CAD). . . . Whether the “self-inflicted DNA breaks” of CAD could contribute to various resistance phenotypes clearly represents a fundamental question that could ultimately give rise to new therapeutic strategies. »
Normal, non-cancerous cells protect themselves from radiation damage through a mechanism that helps them avoid cell division when chromosomes are tangled or broken. “If the parent cell is damaged, the two daughter cells will inherit the damage, and that’s not sustainable in the long term – it’s something that cancer cells also have to avoid,” says cancer biologist Claus Storgaard Sørensen at the University of Copenhagen. and co-author of this study. In cancer cells, however, this mechanism is often dysfunctional. The researchers wanted to understand how cancer cells avoid cell division after radiation.
Of filter using human bone cancer cells, CAD has emerged as a potential player in this process. CAD was already known to break DNA during apoptotic cell death. After irradiating human cancer cell lines, the researchers observed “mysterious nicks” in the DNA of the treated cells, damage that had been hinted at in some “under the radar studies” in the field, Sørensen says. These were not complete breaks or other severe damage, but single-strand breaks occurring 12 to 18 hours after irradiation.
Sørensen and his colleagues found that these notches were dependent on CAD activity. When the team eliminated the enzymatic activity of CAD, the cells became more sensitive to radiation. Cells lacking CAD also entered mitosis prematurely. Additionally, in mice implanted with human tumors, CAD wild-type cells continue to proliferate after radiation, while CAD-deficient tumors “undergo what is largely a state of growth arrest.” extended in response to radiation,” writes Gewirtz. “This is consistent with the hypothesis that CAD-induced pauses provide a survival benefit.”
Sørensen suggests CAD gives cells time to repair radiation damage before dividing. “Maybe CAD creates these easily repairable lesions that could work as a shutdown signal for cancer cells – that cancer cells enforce shutdown just before mitosis, so that the parent cell is protected from division with hard-to-repair radiation damage.” These simple lesions are continuously and rapidly repaired while the parent cell completes the repair of complicated lesions.
CAD activity is typically controlled by caspases, enzymes that facilitate apoptosis. However, the authors find that chemical inhibition of caspase activity does not prevent the formation of DNA nicks. Instead, CAD is always physically associated with its inhibitor ICAD. “CAD, as far as we can tell, moves with the modulator that controls it. This is how cancer cells can probably control it and exploit it,” says Sørensen. “A full-fledged apoptotic pathway. . . it’s not really necessary for this answer.
“What’s new is that they discovered that instead of the caspase-mediated cleavage of ICAD, which leads to the release and activation of CAD, the binary complex itself is recruited to DNA damage sites and then cause secondary damage,” Chuan-Yuan explains. Li, a cancer biologist at Duke University Medical Center who was not involved in the study. “Mechanically, it is unexpected and new that this complex itself has this function.”
Li says he would have liked to see more rigorous testing that CAD-induced single-strand breaks are responsible for radiation protection. In the article, the researchers report finding that cancer cells lacking CAD show increased radiosensitivity and reduced colony growth after radiation. “The colony outgrowth can be explained by alternative effects,” as it takes a week to 10 days for the outgrowth to occur, Li says. longer-term genetic instability or short-term strand breaks.”
The authors developed CAD inhibitors and tested what CAD inhibition might mean for cancer treatment. While cancer cells become more susceptible to radiation damage after CAD inhibition, this effect is not seen in normal cells. “If we inhibit CAD in cancer cells that have hijacked the enzyme and use it for different purposes, we can make cancer cells selectively more sensitive to radiation,” says Sørensen. Additionally, Sørensen believes CAD inhibition can be used to make tumors more visible to the immune system. “Pushing irradiated cells into division helps evoke and display new antigens and enhance immune signaling,” he says, giving immune cells new targets for attack.