Exploring the Metabolic Pathways of Cancer Cells

A study led by researchers at the University of Cincinnati Cancer Center provides new insights into how a key oncogene contributes to the development and progression of lymphoma, potentially informing future targeted therapies.

Study Background

The Cunningham lab focuses on the MYC oncogene, which plays a key role in enhancing the metabolism of cancer cells to support their rapid growth and proliferation. Although many of the individual pathways and functions activated by MYC have been identified, the specific sequence and interactions among these processes remain poorly understood.

Previous studies have shown that MYC directly regulates numerous metabolic pathways involved in maintaining redox homeostasis, the balance between oxidative and reductive states within cells. This balance is essential for proper cellular function and for preventing cell death in cancer cells.

Think of the cell as a battery, and you have got negative charges and positive charges constantly exchanging between molecules and different compartments. A reductive state means that something acquires or gains electrons, and an oxidized state means it loses them.

Tom Cunningham, Associate Professor, Department of Cancer Biology, College of Medicine, University of Cincinnati

An imbalance in oxidative or reductive stress can disrupt redox homeostasis, making cells more vulnerable. As a result, targeting redox processes is one potential strategy for weakening or eliminating cancer cells.

Study Results

The researchers examined the role of the enzyme phosphoribosyl pyrophosphate synthetase (PRPS), which exists in two forms in lymphoma cells: PRPS1 and PRPS2. Using CRISPR gene editing, they selectively removed each form in lymphoma cell line models.

Their findings showed that PRPS1 and PRPS2 perform distinct functions but work together within the same biochemical complex. PRPS2 was found to be more active in lymphoma cells with elevated MYC expression.

The PRPS enzymes and the PRPS complex have a cell-wide effect on redox homeostasis. The many buffering mechanisms in place to regulate redox homeostasis make it very uncommon to find that the difference in catalyzation of a single biochemical reaction produces such a measurable change in the cell’s global redox state, so that was a major surprise.

Austin C. MacMillan, Doctoral Cancer Biology Student, University of Cincinnati

Disabling PRPS2 led to reductive stress in lymphoma cells, while eliminating PRPS1 increased their sensitivity to oxidative stress and cell damage. These results suggest that MYC alters the function of the PRPS complex to support cancer cell survival. However, this metabolic vulnerability could be targeted to enhance the effectiveness of existing or new treatments.

“Disabling PRPS2 turns out to be one of only a handful of loss-of-function strategies we know of that can induce reductive stress,” MacMillan added.

Cunningham stated, “There are so many checks and balances, so many ways of recalibrating that cellular redox state to keep it stable. Discovering that changing flux through the single PRPS enzyme can have such profound consequences on the overall cellular redox state. Having the molecular tools at our disposal to harness that is a really powerful bit of knowledge that we can use in the future.”

The study’s findings support further preclinical testing to identify drugs and pathways that could disrupt redox balance in lymphoma cells. The goal is to advance more effective therapeutic strategies for future clinical trials.

Cunningham noted that the research team is currently developing and testing methods to target the PRPS enzyme. These approaches may eventually be used in combination with therapies such as chemotherapy to treat aggressive MYC-driven lymphomas.