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

Document Type : Original Article


Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang Province, China


Objective: Drug resistance is the main hindrance to improve the prognosis of patients with gastric cancer. Amino
acid 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 novo
biosynthesis of serine, phosphoglycerate dehydrogenase (PHGDH) inhibition could also induce cisplatin resistance in
gastric cancer. This study aims to reveal the potential mechanisms of drug resistance induced by PHGDH inhibition via
exploring the global mRNA expression profiles.
Materials and Methods: In this experimental study, the viability and the apoptotic rate of gastric cancer cells
were evaluated by using Cell Counting Kit-8 (CCK-8) analysis and flow cytometric determination, respectively. The
identification of differentially expressed genes (DEGs) was tested by mRNA-sequencing (mRNA-Seq) analysis. The
confirmation of sequencing results was verified using real-time quantitative reverse transcription polymerase chain
reaction (RT-qPCR).
Results: The inhibition of PHGDH significantly increased the viability and decreased the apoptotic rate induced by cisplatin
in gastric cancer cells. mRNA-Seq analysis revealed that the combined treatment of NCT503 reduced the number of DEGs
induced by cisplatin. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment
Analysis (GSEA) showed that unfolded protein response, ECM receptor interaction and cell cycle signaling pathways were
modulated 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 cancer
through various intercellular mechanisms. And appropriate serine supplementation or the modulation of EP300 and
HSPA8 may be of great help in overcoming cisplatin resistance in gastric cancer.


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