A recent study published in Oncotarget, Volume 16, on February 18, 2025, titled “Robust p53 phenotypes and prospective downstream targets in telomerase-immortalized human cells,” offers valuable insights into the role of p53, a crucial tumor-suppressing protein. Researchers Jessica J. Miciak, Lucy Petrova, Rhythm Sajwan, Aditya Pandya, Mikayla Deckard, Andrew J. Munoz, and Fred Bunz from the Sidney Kimmel Comprehensive Cancer Center and Johns Hopkins University School of Medicine conducted this study.
The p53 protein is vital in preventing cancer by halting uncontrolled cell growth. However, many cancers mutate or suppress p53, enabling tumor development and resistance to treatment. In their research, the team restored p53 function in colorectal cancer cells, resulting in slower cellular growth, increased cellular aging (senescence), and greater sensitivity to radiation therapy. These findings suggest that p53 status influences both cancer progression and response to treatment, making it an attractive target for new therapies.
The study also examined hTERT-RPE1 cells—non-cancerous human cells used in research—to further understand the impact of disrupted TP53 genes. When this gene was disabled, these cells grew faster and became more resistant to radiation. This observation reinforces the role of p53 in preventing cancerous growth.
Another significant discovery was a previously unidentified p53 mutation (A276P) found in some hTERT-RPE1 cells. Although this mutation impaired p53’s ability to regulate certain genes, it did not affect its function regarding calcium signaling, which is crucial for cell survival. This unexpected genetic change suggests that even non-cancerous cells can develop alterations similar to early cancer stages. Understanding these changes could provide better insights into how cancers evolve and become resistant to treatment.
“Cancers that retain wild type TP53 presumably harbor other clonal alterations that permitted their precursors to bypass p53-mediated growth suppression,” the researchers noted, indicating a complex interplay of genetic factors in cancer development.
A breakthrough in the study was identifying two new genes regulated by p53 with potential applications for cancer treatment. The first gene, ALDH3A1, aids in detoxifying harmful substances and may impact how cancer cells resist oxidative stress. The second is NECTIN4, a protein present in many aggressive cancers like bladder and breast cancer. Notably, NECTIN4 is the target of enfortumab vedotin, an FDA-approved drug for treating bladder cancer.
These findings offer new potential drug targets that could lead to improved therapies for cancers still retaining some p53 function. By leveraging these discoveries, researchers may develop more effective precision medicine strategies that take advantage of p53’s natural tumor-suppressing abilities.
In conclusion, this research underscores the critical role of p53 in cancer biology and suggests that restoring its function could make tumors more vulnerable to radiation therapy and chemotherapy. Further exploration into new genes controlled by p53 provides exciting opportunities for targeted cancer therapies.
