What is it about?
Cancer cells need a constant supply of nutrients to grow and spread. One important nutrient is serine, an amino acid that cells can either make themselves or absorb from their surroundings. How cancer cells decide between these two sources has remained unclear. In this study, we discovered that a protein called PLK1, which is often present at high levels in advanced prostate cancer, changes the way cancer cells obtain serine. PLK1 switches off the cell's own serine production by modifying another protein called PHGDH, the enzyme that starts the serine production pathway. As a result, cancer cells become more dependent on absorbing serine from their environment through the transporter ASCT2. Rather than simply replacing the lost serine, this imported serine is redirected into the production of sphingolipids, a group of fats that help cancer cells survive and continue growing. This metabolic switch reveals that advanced prostate cancer cells can adapt their nutrient use to support tumor progression. Our findings identify a previously unknown link between cell division signals and cancer metabolism. They also suggest that blocking serine uptake, restoring serine production, or interfering with sphingolipid synthesis could provide new treatment strategies for aggressive prostate cancer with high PLK1 activity.
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Why is it important?
Cancer cells often change the way they use nutrients to survive, grow, and resist treatment. Although serine metabolism has become an important focus of cancer research, it has remained unclear how cancer cells switch between making their own serine and obtaining it from their surroundings. Our study identifies a previously unrecognized mechanism that controls this decision. We show that the cancer-associated kinase PLK1 directly modifies the metabolic enzyme PHGDH, suppressing the cell's own serine production and shifting cancer cells toward dependence on serine uptake from their environment. This imported serine is then redirected to support the production of sphingolipids, molecules that contribute to tumor growth and survival. This work is timely because targeting cancer metabolism has emerged as a promising therapeutic strategy, and several drugs that inhibit PLK1, serine metabolism, or amino acid transport are already under clinical or preclinical investigation. By revealing how these pathways are mechanistically connected, our findings provide a framework for identifying patients who may benefit from metabolism-based therapies and suggest new combination treatment strategies for advanced prostate cancer. More broadly, this study expands our understanding of how cancer-promoting signaling pathways directly reprogram cellular metabolism, a concept that may be relevant to many other tumor types.
Perspectives
What I find most exciting about this study is that it challenges a common assumption in cancer metabolism—that increased tumor growth is always accompanied by increased production of nutrients within the cancer cell. Instead, our findings suggest that advanced prostate cancer can benefit from doing the opposite. By suppressing its own serine synthesis through PLK1-dependent phosphorylation of PHGDH, the tumor becomes more dependent on acquiring serine from its environment and redirects this nutrient toward lipid pathways that support its growth. I also find it fascinating that a well-known cell cycle kinase can directly reshape metabolic decisions. This highlights how signaling pathways and metabolism are more tightly integrated than we often appreciate. Rather than viewing these processes separately, I believe understanding their coordination will be essential for uncovering new therapeutic vulnerabilities. I hope this work encourages researchers to think beyond individual metabolic enzymes and consider how signaling networks determine where nutrients come from and how they are ultimately used. If these findings stimulate new studies of nutrient-source switching or inspire combination therapies that target both signaling and metabolism, I will consider that an important contribution of this work.
Xiongjian Rao
University of Kentucky
Read the Original
This page is a summary of: PLK1-mediated phosphorylation of PHGDH reprograms serine metabolism in advanced prostate cancer, Proceedings of the National Academy of Sciences, July 2026, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2618349123.
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