Restricting Metabolic Plasticity Enhances Stress Adaptation Through the Modulation of Pdh and HIF1A in TRAP1-Depleted Colon Cancer

Authors

Hong-Yuan Tsai
Miao-Hsueh Chen
Jihye Yun
Lisa A Lai
John F Valentine
Mary P Bronner
Teresa A Brentnall
Sheng Pan
Ru Chen

Language

English

Publication Date

11-1-2025

Journal

Cancer Letters

DOI

10.1016/j.canlet.2025.217977

PMID

40789509

PMCID

PMC12582411

PubMedCentral® Posted Date

11-4-2025

PubMedCentral® Full Text Version

Author MSS

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

Colonic Neoplasms, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Glycolysis, Glucose Transporter Type 1, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Cell Line, Tumor, Oxidative Phosphorylation, HCT116 Cells, Reactive Oxygen Species, Gene Expression Regulation, Neoplastic, Monocarboxylic Acid Transporters, Adaptation, Physiological, CRISPR-Cas Systems, HSP90 Heat-Shock Proteins, Symporters, Monocarboxylate Transport Protein 1, TRAP1, Metabolism, Mitochondria, ROS, HIF1A, PDH

Published Open-Access

yes

Recommended Citation

Tsai, Hong-Yuan; Chen, Miao-Hsueh; Yun, Jihye; et al., "Restricting Metabolic Plasticity Enhances Stress Adaptation Through the Modulation of Pdh and HIF1A in TRAP1-Depleted Colon Cancer" (2025). Faculty, Staff and Student Publications. 6390.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6390