Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Pan, Kailing, Zhao, Xiaoya, Xu, Wenxia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royan Institute 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9594867/
https://www.ncbi.nlm.nih.gov/pubmed/36274206
http://dx.doi.org/10.22074/cellj.2022.8046
_version_ 1784815527299907584
author Pan, Kailing
Zhao, Xiaoya
Xu, Wenxia
author_facet Pan, Kailing
Zhao, Xiaoya
Xu, Wenxia
author_sort Pan, Kailing
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9594867
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Royan Institute
record_format MEDLINE/PubMed
spelling pubmed-95948672022-10-28 The Global mRNA Expression Profiles of Inhibiting PHGDH Induced Cisplatin Resistance in Gastric Cancer Pan, Kailing Zhao, Xiaoya Xu, Wenxia Cell J Original Article 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. Royan Institute 2022-09 2022-09-12 /pmc/articles/PMC9594867/ /pubmed/36274206 http://dx.doi.org/10.22074/cellj.2022.8046 Text en Any use, distribution, reproduction or abstract of this publication in any medium, with the exception of commercial purposes, is permitted provided the original work is properly cited. https://creativecommons.org/licenses/by-nc/3.0/This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial 3.0 (CC BY-NC 3.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Pan, Kailing
Zhao, Xiaoya
Xu, Wenxia
The Global mRNA Expression Profiles of Inhibiting PHGDH Induced Cisplatin Resistance in Gastric Cancer
title The Global mRNA Expression Profiles of Inhibiting PHGDH Induced Cisplatin Resistance in Gastric Cancer
title_full The Global mRNA Expression Profiles of Inhibiting PHGDH Induced Cisplatin Resistance in Gastric Cancer
title_fullStr The Global mRNA Expression Profiles of Inhibiting PHGDH Induced Cisplatin Resistance in Gastric Cancer
title_full_unstemmed The Global mRNA Expression Profiles of Inhibiting PHGDH Induced Cisplatin Resistance in Gastric Cancer
title_short The Global mRNA Expression Profiles of Inhibiting PHGDH Induced Cisplatin Resistance in Gastric Cancer
title_sort global mrna expression profiles of inhibiting phgdh induced cisplatin resistance in gastric cancer
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9594867/
https://www.ncbi.nlm.nih.gov/pubmed/36274206
http://dx.doi.org/10.22074/cellj.2022.8046
work_keys_str_mv AT pankailing theglobalmrnaexpressionprofilesofinhibitingphgdhinducedcisplatinresistanceingastriccancer
AT zhaoxiaoya theglobalmrnaexpressionprofilesofinhibitingphgdhinducedcisplatinresistanceingastriccancer
AT xuwenxia theglobalmrnaexpressionprofilesofinhibitingphgdhinducedcisplatinresistanceingastriccancer
AT pankailing globalmrnaexpressionprofilesofinhibitingphgdhinducedcisplatinresistanceingastriccancer
AT zhaoxiaoya globalmrnaexpressionprofilesofinhibitingphgdhinducedcisplatinresistanceingastriccancer
AT xuwenxia globalmrnaexpressionprofilesofinhibitingphgdhinducedcisplatinresistanceingastriccancer