The Global mRNA Expression Profiles of Inhibiting PHGDH Induced Cisplatin Resistance in Gastric Cancer

Abstract

Objective: Drug resistance is the main hindrance to improve the prognosis of patients with gastric cancer. Aminoacid metabolic reprograming is essential to satisfy the different requirements of cancer cells during drug resistance,of which serine deprivation could promote resistance to cisplatin in gastric cancer. As the key enzyme in the de novobiosynthesis of serine, phosphoglycerate dehydrogenase (PHGDH) inhibition could also induce cisplatin resistance ingastric cancer. This study aims to reveal the potential mechanisms of drug resistance induced by PHGDH inhibition viaexploring the global mRNA expression profiles.Materials and Methods: In this experimental study, the viability and the apoptotic rate of gastric cancer cellswere evaluated by using Cell Counting Kit-8 (CCK-8) analysis and flow cytometric determination, respectively. Theidentification of differentially expressed genes (DEGs) was tested by mRNA-sequencing (mRNA-Seq) analysis. Theconfirmation of sequencing results was verified using real-time quantitative reverse transcription polymerase chainreaction (RT-qPCR).Results: The inhibition of PHGDH significantly increased the viability and decreased the apoptotic rate induced by cisplatinin gastric cancer cells. mRNA-Seq analysis revealed that the combined treatment of NCT503 reduced the number of DEGsinduced by cisplatin. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set EnrichmentAnalysis (GSEA) showed that unfolded protein response, ECM receptor interaction and cell cycle signaling pathways weremodulated by NCT503 treatment. Hub genes were identified by using protein-protein interaction network modeling, of which E1A binding protein p300 (EP300) and heat shock protein family A (Hsp70) member 8 (HSPA8) act as the vital genes in cisplatin resistance induced by the inhibition of PHGDH.Conclusion: These findings suggested that the inhibition of PHGDH promoted cisplatin resistance in gastric cancerthrough various intercellular mechanisms. And appropriate serine supplementation or the modulation of EP300 andHSPA8 may be of great help in overcoming cisplatin resistance in gastric cancer.

Keywords

• cisplatin
• drug resistance
• gastric cancer
• phosphoglycerate dehydrogenase