2. Academic Validation
  3. Restricting metabolic plasticity enhances stress adaptation through the modulation of PDH and HIF1A in TRAP1-depleted colon cancer

Restricting metabolic plasticity enhances stress adaptation through the modulation of PDH and HIF1A in TRAP1-depleted colon cancer

  • Cancer Lett. 2025 Aug 9:632:217977. doi: 10.1016/j.canlet.2025.217977.
Hong-Yuan Tsai 1,  Miao-Hsueh Chen 2,  Jihye Yun 3,  Lisa A Lai 4,  John F Valentine 5,  Mary P Bronner 6,  Teresa A Brentnall 4,  Sheng Pan 7,  Ru Chen 8
Affiliations

Affiliations

  • 1 Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA. Electronic address: hong-yuan.tsai@bcm.edu.
  • 2 USDA/ARS, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
  • 3 Department of Genetics, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Department of Medicine, University of Washington, Seattle, WA, USA.
  • 5 Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Utah, Salt Lake City, UT, USA.
  • 6 Department of Pathology, University of Utah, Salt Lake City, UT, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • 7 Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA; Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 8 Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA. Electronic address: ru.chen@bcm.edu.
PMID: 40789509 DOI: 10.1016/j.canlet.2025.217977
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.

Keywords

HIF1A; Metabolism; Mitochondria; PDH; ROS; TRAP1.

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    Gamitrinib Mitochondrial Matrix Inhibitor
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