Inhibition of Phosphoglycerate Dehydrogenase Radiosensitizes Human Colorectal Cancer Cells under Hypoxic Conditions

Melissa Van de Gucht, Inès Dufait, Lisa Kerkhove, Cyril Corbet, Sven de Mey, Heng Jiang, Ka Lun Law, Thierry Gevaert, Olivier Feron, Mark De Ridder

Research output: Contribution to journalArticlepeer-review

Abstract

Augmented de novo serine synthesis activity is increasingly apparent in distinct types of cancers and has mainly sparked interest by investigation of phosphoglycerate dehydrogenase (PHGDH). Overexpression of PHGDH has been associated with higher tumor grade, shorter relapse time and decreased overall survival. It is well known that therapeutic outcomes in cancer patients can be improved by reprogramming metabolic pathways in combination with standard treatment options, for example, radiotherapy. In this study, possible metabolic changes related to radioresponse were explored upon PHGDH inhibition. Additionally, we evaluated whether PHGDH inhibition could improve radioresponse in human colorectal cancer cell lines in both aerobic and radiobiological relevant hypoxic conditions. Dysregulation of reactive oxygen species (ROS) homeostasis and dysfunction in mitochondrial energy metabolism and oxygen consumption rate were indicative of potential radiomodulatory effects. We demonstrated that PHGDH inhibition radiosensitized hypoxic human colorectal cancer cells while leaving intrinsic radiosensitivity unaffected. In a xenograft model, the first hints of additive effects between PHGDH inhibition and radiotherapy were demonstrated. In conclusion, this study is the first to show that modulation of de novo serine biosynthesis enhances radioresponse in hypoxic colorectal cancer cells, mainly mediated by increased levels of intracellular ROS.

Original languageEnglish
Article number5060
Number of pages17
JournalCancers
Volume14
Issue number20
DOIs
Publication statusPublished - Oct 2022

Bibliographical note

Funding Information:
This work was supported by the strategic research program “Societal Benefit of Markerless Stereotactic Body Radiotherapy: A Statistical Support based on Quantitative Imaging” (Zwaartepunt, SRP 53, 2019–2024) of the research council of the Vrije Universiteit Brussel.

Publisher Copyright:
© 2022 by the authors.

Copyright:
Copyright 2022 Elsevier B.V., All rights reserved.

Keywords

  • colorectal cancer
  • hypoxia
  • radiosensitivity
  • reactive oxygen species
  • serine synthesis pathway

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