Ming Chen, PhD, is the senior author of a paper he co-authored with recent Duke Pathology PhD graduate Zoe Loh, PhD, published on Aug. 11th, 2023 in Metabolites titled “Nuclear PTEN Regulates Thymidylate Biosynthesis in Human Prostate Cancer Cell Lines.”
Metabolic reprogramming contributes to tumorigenesis and holds significant promise for targeted cancer therapy. Metabolism must be compartmentalized to avoid futile cycles and to direct metabolic flow towards the correct output.
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is among the most frequently lost or mutated tumor suppressor genes in human cancer. In the cytoplasm, PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K) signaling pathway to regulate a variety of biological processes, including metabolism. PTEN also accumulates in the nucleus. However, whether PTEN regulates metabolism in the nucleus, and what metabolic vulnerabilities may exist in cells lacking nuclear PTEN, remain unknown.
Using a gain-of-function approach to targeting PTEN to the plasma membrane and nucleus, Chen and colleagues, including first author and Chen Lab member Loh, discovered that one of the top metabolic pathways regulated by nuclear PTEN is pyrimidine metabolism, in particular de novo thymidylate biosynthesis - a metabolic pathway that is harnessed by antifolates for cancer treatment.
“The nucleus is a central hub for metabolism that allows for local control of the core metabolites needed for cell growth/division and the regulation of the epigenome.” said Chen. “This is the first study to define the metabolic regulation of PTEN in the nucleus.”
The absence of nuclear PTEN is associated with more aggressive cancers, suggesting that its function in the nucleus is as relevant to tumor suppression as modulation of the PI3K/AKT signaling in the cytoplasm. Interestingly, impaired thymidylate synthesis is known to increase rates of uracil misincorporation into DNA, leading to genomic instability, and to sensitize cells to antifolate treatment. The study by the Chen Lab not only suggests a potential new mechanism underlying PTEN-mediated genomic stability but also has implications for targeting nuclear-excluded PTEN cancer cells with antifolate drugs.
Funding for this study was provided by National Institutes of Health (NIH) grant R01 CA261949.