MedicalResearch: What is the background for this study? What are the main findings?
Dr. Aird: Senescence is considered an important tumor suppressor mechanism. In normal cells, activation of certain oncogenes decreases the levels of dNTPs (the building blocks of DNA), leading to replication stress. We previously found that loss of the rate-limiting enzyme in dNTP synthesis, ribonucleotide reductase M2 (RRM2), is the cause of this replication stress. Restoration of RRM2 expression could rescue the loss of dNTPs and replication stress, which overcame the senescence-associated growth arrest. Indeed, RRM2 is highly expressed in many cancer types, including melanoma and ovarian cancer. Therefore, we found that increased dNTP levels can overcome senescence and potentially lead to transformation of cells and cancer.
We next wanted to further our understanding of replication stress in the context of senescence. In the current study, we suppressed nucleotide metabolism by decreasing RRM2 expression as a model for replication stress and then determined what proteins are necessary for the induction of senescence. We found that loss of ATM could overcome replication stress-induced senescence. This was due to increased dNTP levels. dNTPs were increased due to a coordinated inactivation of p53 and activation of c-MYC by loss of ATM. These changes at the molecular level correlate with reprogramming of cellular metabolism by generating dNTPs. Thus, loss of ATM in the context of replication stress can change cellular metabolism to a more cancer-like phenotype.
MedicalResearch: What should clinicians and patients take away from your report?
Dr. Aird: Understanding how cells overcome senescence may allow for new therapeutic strategies to target these cells. Knowledge of these pathways may even allow for us to prevent these cells from becoming cancer. However, it is important to stress that our observation is just one of many potential ways cells could overcome senescence. A comprehensive study is needed to explore ways of targeting the common threads to benefit a larger subset of patients.
MedicalResearch: What recommendations do you have for future research as a result of this study?
Dr. Aird: Here, we identified a novel pathway whereby loss of ATM, which occurs in a number of human cancers, can overcome senescence by reprogramming cellular metabolism. It is therefore possible that patients with loss or mutations in ATM may benefit from metabolism-targeting therapeutics. This is the next step we will need to take to ultimately determine whether any metabolism-targeting cancer therapeutics can be derived from our current study.
MedicalResearch.com Interview with: Katherine Aird, Ph.D. (2015). Study Identifies One Pathway Cancer Cells Use To Evade Death MedicalResearch.com