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

SIMPLE SUMMARY: Colorectal cancer is the third most prevalent cancer worldwide. Treatment options for these patients consist of surgery combined with chemotherapy and/or radiotherapy. However, a subset of tumors will not respond to therapy or acquire resistance during the course of the treatment, leading to patient relapse. The interplay between reprogramming cancer metabolism and radiotherapy has become an appealing strategy to improve a patient’s outcome. Due to the overexpression of certain enzymes in a variety of cancer types, including colorectal cancer, the serine synthesis pathway has recently become an attractive metabolic target. We demonstrated that by inhibiting the first enzyme of this pathway, namely phosphoglycerate dehydrogenase (PHGDH), tumor cells that are deprived of oxygen (as is generally the case in solid tumors) respond better to radiation, leading to increased tumor cell killing in an experimental model of human colorectal cancer. 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.