Inhibition of PDK modulates radiotherapy resistance in gastric cancer

Abstract

Abstract To explore the effect of sodium dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, on the progression of gastric cancer and resistance to radiotherapy, we analyzed histopathological microarrays from 60 gastric cancer and paracancerous tissues to determine PDK expression and its prognostic significance. 5-Ethynyl-2′-deoxyuridine (EdU) incorporation assay and Transwell migration assay were used to investigate the effects of PDK inhibition on gastric cancer cell proliferation and migration. Flow cytometry revealed that PDK inhibition promoted apoptosis and induced G1 phase cell cycle arrest. Colony formation assay combined with radiation was performed to calculate radiobiological parameters, while Western blot detected the expression of phosphorylated histone H2AX (γ-H2AX), a DNA double-strand break marker. Reactive oxygen species (ROS) generation was measured using the fluorescent probe 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA). Our results showed that PDK was highly expressed in gastric cancer tissues and correlated with poor patient prognosis. PDK inhibition suppressed proliferation and migration of gastric cancer cells, promoted apoptosis and G1 phase arrest, and enhanced γ-H2AX accumulation and ROS generation, thereby increasing radiosensitivity. These findings demonstrate that targeting PDK inhibits gastric cancer progression and sensitizes tumor cells to radiotherapy.

Keywords

• Gastric cancer
• DCA
• PDK
• Glycolysis
• Radiotherapy resistance