In the ongoing battle against cancer, innovative therapies like immunotherapy and targeted treatments have emerged, but traditional methods like radiation and chemotherapy still remain the frontline options for many patients. These treatments work by damaging the DNA of cancer cells, exploiting their weakened ability to repair DNA compared to healthy cells. In an ideal scenario, cancer cells exposed to radiation or chemotherapy undergo apoptosis or die due to the accumulated DNA damage.
However, there is another possible outcome for cancer cells after DNA damage: a state called senescence. In this state, the cells survive but cease to divide. Although senescent cancer cells cannot proliferate and spread, they can have negative effects on surrounding cancer cells, potentially enabling them to become more aggressive.
A recent study conducted by MIT researchers sheds light on the process by which cancer cells decide to undergo senescence after treatment with certain low doses of chemotherapy. The researchers found that cell signaling proteins, typically associated with cell proliferation and apoptosis, instead play a role in committing cancer cells to senescence within just 12 hours of exposure to specific chemotherapy agents.
The study involved experiments with ovarian and osteosarcoma cancer cells, as well as computational modeling. Two protein kinases (MAP kinases Erk and JNK) and a component of the AP-1 transcription factor complex were identified as crucial factors in inducing senescence after DNA damage. These proteins are known to promote cell proliferation in cancer, making the findings surprising and significant.
The researchers used doxorubicin, a common chemotherapy drug that disrupts the function of topoisomerase II, an enzyme involved in repairing DNA strands during replication. By tracking cell fate over time and measuring cell signaling activity levels, the team constructed a computational model that revealed correlations between time, dosage, signaling, and cell fate. Inhibiting JNK and Erk after DNA damage prevented cells from entering senescence, confirming the model’s predictions.
Interestingly, the decision for cells to enter senescence was made within 12 hours of DNA damage, even though it took several days to observe the accumulation of senescent cells. As time passed, MAP kinases took on a different role, promoting the secretion of proinflammatory cytokines, which stimulate neighboring cancer cells to proliferate and develop resistance to chemotherapy.
These findings highlight the importance of understanding the molecular characteristics of cancer cells and the contextual factors, such as timing and dosing, that influence cell fate during cancer treatment. The study also warns against combining MEK inhibitors, a class of Erk inhibitors, with chemotherapies, as this combination could unintentionally drive cells into proliferation instead of senescence.
In future research, the team plans to investigate why certain individual cells choose proliferation over senescence and identify the specific genes regulated by c-Jun, a component of the AP-1 transcription factor complex, to promote senescence in cancer cells.
Overall, this study enhances our understanding of cancer cell behavior in response to chemotherapy and emphasizes the need for a more nuanced approach to cancer treatment, taking into account the complex molecular mechanisms that determine cell fate.