A groundbreaking study led by researchers at the University of Cincinnati Cancer Center has unveiled novel insights into the intricate molecular mechanisms by which the oncogene MYC orchestrates the development and progression of lymphoma. This research sheds light on how MYC reprograms cancer cell metabolism to maintain a precarious balance of redox homeostasis, a fundamental aspect that supports the survival and aggressive proliferation of lymphoma cells. These findings promise to transform therapeutic strategies and open avenues for targeted interventions that exploit vulnerabilities in cancer metabolism.
The study, published on May 29 in the journal Redox Biology, is spearheaded by doctoral candidate Austin C. MacMillan and senior investigator Tom Cunningham, PhD, whose laboratory focuses on deciphering the complex biochemical pathways driven by oncogenes. MYC, often described as a master regulator, revs up the metabolic machinery of cancer cells, fueling their explosive growth. However, despite extensive knowledge about the individual pathways influenced by MYC, the precise orchestration and coordination of these metabolic networks have remained elusive, particularly their role in manipulating the redox state of lymphoma cells.
At the heart of redox biology lies the delicate equilibrium between oxidative and reductive processes—an essential balance for cell function and survival. Cells maintain this balance through a tightly regulated exchange of electrons, akin to a cellular battery cycling between charged and discharged states. An oxidative state reflects electron loss, while a reductive state reflects electron gain. Cancer cells, under the influence of MYC, manipulate this redox balance to prevent oxidative damage and sustain unchecked proliferation. Disrupting this homeostasis offers a promising avenue to selectively weaken or kill cancer cells without harming normal tissue.
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The research team focused on a pivotal enzyme complex known as phosphoribosyl pyrophosphate synthetase (PRPS), which exists in two isoforms in lymphoma cells: PRPS1 and PRPS2. These enzymes regulate the synthesis of phosphoribosyl pyrophosphate (PRPP), a key metabolite for nucleotide biosynthesis and other crucial cellular functions. Utilizing cutting-edge CRISPR-Cas9 gene-editing technology, the researchers selectively knocked out each isoform in lymphoma cell models, enabling them to delineate the distinct and overlapping roles of PRPS1 and PRPS2 in regulating cellular metabolism and redox balance.
The experiments revealed that while both PRPS1 and PRPS2 are vital to lymphoma pathophysiology, they perform differential yet collaborative roles within a biochemical complex profoundly impacting cellular redox homeostasis. Notably, PRPS2 expression and activity were significantly upregulated in lymphoma cells with MYC overexpression, suggesting that MYC co-opts this enzyme complex to remodel metabolic fluxes for its oncogenic agenda. This remodeling alters redox buffering capacity, helping cancer cells to tolerate oxidative stress inflicted by their rapid growth and hostile microenvironment.
Dr. MacMillan elaborates on the surprising discovery that modulation of a single enzymatic step by PRPS can induce widespread alterations in cellular redox states. “We typically expect metabolic networks to exhibit substantial redundancy and buffering capacity, making it rare for one enzymatic activity to exert such global influence.” Yet, the team observed that disrupting PRPS1 heightened cellular sensitivity to oxidative stress, culminating in increased damage within lymphoma cells, whereas abrogation of PRPS2 led to a paradoxical shift toward reductive stress—an accumulation of reducing equivalents that can itself be cytotoxic.
Understanding this dualistic role is pivotal because it demonstrates that MYC-driven lymphoma cells rely on a finely tuned PRPS complex to maintain redox equilibrium, which is essential for their survival. Targeting this enzymatic hub holds therapeutic promise. By strategically inhibiting PRPS enzymes, researchers envision pushing lymphoma cells beyond their narrow window of redox tolerance, selectively triggering cell death or sensitizing tumors to existing chemotherapies and novel oxidative stress-inducing agents.
Professor Cunningham highlights the translational potential of these insights: “The interplay between MYC and the PRPS complex offers a unique metabolic vulnerability. Therapeutic strategies that disrupt this interface have the potential to destabilize cancer cell metabolism profoundly.” The team is currently developing molecular tools and small molecule inhibitors to manipulate PRPS activity with precision. Such agents could be integrated into combination therapy regimens aimed at eradicating resistant and aggressive lymphomas characterized by MYC overexpression.
Another intriguing aspect of the study is the identification of PRPS2 loss as one of the rare few genetic manipulations capable of inducing reductive stress. This phenomenon occurs when excessive reducing agents accumulate, perturbing cellular function and leading to a distinct form of stress that can be therapeutically exploited. Because cancer metabolism is notoriously adaptable, having multiple strategies to tip the redox balance abnormally equips researchers with a broader arsenal against lymphoma.
Through preclinical screening, the lab plans to identify additional compounds and molecular pathways that synergize with PRPS inhibition to further destabilize lymphoma cells’ redox systems. These efforts aim to create a new generation of targeted therapies that go beyond broad cytotoxic approaches, minimizing collateral damage and improving patient outcomes. The integration of metabolic and redox biology thus holds promise for highly selective cancer therapeutics.
The publication also clarifies conflict of interest statements: MacMillan and Cunningham have filed a patent application related to this research, underscoring the innovative translational potential of their findings. Other authors involved in the study declared no competing interests. The collaborative team includes Bibek Karki, Juechen Yang, Karmela Gertz, Samantha Zumwalde, Jay Patel, Maria Czyzyk-Krzeska, and Jarek Meller.
Given the critical role of MYC in diverse cancers, the implications of tuning PRPS-mediated redox homeostasis transcend lymphoma and may inspire broader oncological research. The study exemplifies how unraveling metabolic interdependencies can reveal hidden vulnerabilities, providing a conceptual blueprint for next-generation cancer therapies that exploit the bioenergetic and redox peculiarities of tumor cells.
As lymphoma remains a significant clinical challenge with often limited treatment options for aggressive forms, this research represents hope for patients and clinicians alike. By harnessing insights into redox biology and metabolic control, the scientific community advances closer to therapies that not only inhibit cancer growth but do so with precision and adaptability, reducing the burden of side effects and overcoming resistance.
This landmark study highlights the power of combining innovative genetic tools, rigorous biochemical analysis, and an integrative understanding of cancer metabolism. It stands at the forefront of an evolving landscape where cancer treatment transitions from broad-spectrum cytotoxicity to exquisitely targeted metabolic intervention, setting a new paradigm in oncology research.
Subject of Research:
Metabolic regulation and redox homeostasis in MYC-driven lymphoma mediated by phosphoribosyl pyrophosphate synthetase (PRPS) enzyme complex.
Article Title:
PRPS activity tunes redox homeostasis in Myc-driven lymphoma
News Publication Date:
29-May-2025
Web References:
https://doi.org/10.1016/j.redox.2025.103649
Image Credits:
Photo: University of Cincinnati
Keywords:
Lymphoma, Cancer metabolism, Redox homeostasis, MYC oncogene, PRPS1, PRPS2, CRISPR gene editing, Phosphoribosyl pyrophosphate synthetase, Oxidative stress, Reductive stress, Cancer therapeutics, Metabolic vulnerabilities
Tags: biochemical pathways in oncologycancer cell metabolism reprogrammingcancer survival mechanismslymphoma progression mechanismsmetabolic vulnerabilities in lymphomaMYC oncogene and lymphomaoxidative and reductive processes balanceredox biology researchredox homeostasis in cancertargeted cancer therapiestherapeutic strategies for lymphomaUniversity of Cincinnati Cancer Center study