Restricting metabolic plasticity enhances stress adaptation through the modulation of PDH and HIFIA in TRAP1-depleted colon cancer

Authors: TSAI, HONG-YUAN - Baylor College Of Medicine; CHEN, MIAO-HSUEH - Children'S Nutrition Research Center (CNRC); YUN, JIHYE - Md Anderson Cancer Center; LAI, LISA - University Of Washington School Of Medicine; VALENTINE, JOHN - University Of Utah; BRONNER, MARY - University Of Utah; BRENTNAIL, TERESA - University Of Washington School Of Medicine; PAN, SENG - University Of Texas Health Science Center; CHEN, RU - Baylor College Of Medicine

Submitted to: Cancer Letters
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/7/2025
Publication Date: 8/9/2025
Citation: Tsai, H., Chen, M., Yun, J., Lai, L.A., Valentine, J.F., Bronner, M.P., Brentnail, T.A., Pan, S., Chen, R. 2025. Restricting metabolic plasticity enhances stress adaptation through the modulation of PDH and HIFIA in TRAP1-depleted colon cancer. Cancer Letters. 632. Article 217977. https://doi.org/10.1016/j.canlet.2025.217977.
DOI: https://doi.org/10.1016/j.canlet.2025.217977

Interpretive Summary: Researchers in Houston, Texas studied how cancer cells change the way they use energy when they are under stress. It was not clear how a protein called TRAP1 helps cancer cells survive, and this matters because these cells can resist treatment and continue to grow. Before this work, scientists knew that cancer cells could switch how they make energy, but the role of TRAP1 in this process was not well understood. The researchers removed TRAP1 from colon cancer cells and found that the cells relied more on sugar for energy, produced more acid waste, and handled stress better, but became easier to kill when a specific drug blocked this new pathway. These findings show that targeting this energy shift may help make cancer treatments work better. This work links to USDA/ARS priorities by improving understanding of how cells use nutrients like glucose, which supports research on diet and health and helps guide precision nutrition.

Technical Abstract: Metabolic plasticity allows cancer cells to survive under adverse conditions. To investigate the role of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) in this process, we used CRISPR/Cas9 mediated genetic deletion to knock out (KO) TRAP1 in colon cancer cells. Depletion of TRAP1 triggered a series of events: induced metabolic reprogramming, increased glycolytic flux, downregulation of mitochondrial complex I, and elevated ROS generation. TRAP1-deficient cells showed tolerance to Oxidative Phosphorylation (OXPHOS) inhibitors and exhibited a higher extracellular acidification rate (ECAR). Additionally, TRAP1 depletion activated hypoxia response elements (HREs) and upregulated HIF1A target genes such as GLUT1 and MCT1. Furthermore, pyruvate dehydrogenase kinases 1 (PDK1) was upregulated in KO cells, leading to the inactivation of the tricarboxylic acid (TCA) cycle enzyme, pyruvate dehydrogenase (PDH). This metabolic shift towards glycolytic metabolism resulted in increased glycolytic metabolism, elevated lactic acid production, and higher glucose consumption, making TRAP1-depleted cancer cells more dependent on this altered metabolism for survival. Treatment with DCA, a PDK inhibitor, restored PDH activity, exacerbated oxidative stress, and increased cell death in KO cells. Our study here sheds light on how TRAP1 depletion affects metabolic plasticity, driving colon cancer cells to adapt to metabolic and oxidative stress. These findings highlight TRAP1 as a promising therapeutic target for manipulating metabolic plasticity and overcoming drug resistance in cancer therapy.