Identification of novel drug resistance mechanisms by genomic and transcriptomic profiling of glioblastoma cells with mutation-activated EGFR

Publication type:
Journal article
Metadata:
Autoren
  • Onat Kadioglu
  • Mohamed EM Saeed
  • Nuha Mahmoud
  • Shaymaa Azawi
  • Kristin Mrasek
  • Thomas Liehr
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000704334500003&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.lfs.2021.119601
eISSN
1879-0631
Externe Identifier
  • Clarivate Analytics Document Solution ID: WC5YV
  • PubMed Identifier: 33991550
ISSN
0024-3205
Zeitschrift
LIFE SCIENCES
Schlüsselwörter
  • Cancer
  • Chromosomal aberrations
  • Drug resistance
  • Oncogenes
  • Transcriptomics
Artikelnummer
ARTN 119601
Datum der Veröffentlichung
2021
Status
Published
Titel
Identification of novel drug resistance mechanisms by genomic and transcriptomic profiling of glioblastoma cells with mutation-activated EGFR
Sub types
  • Article
Ausgabe der Zeitschrift
284

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Onat Kadioglu
  • Mohamed EM Saeed
  • Nuha Mahmoud
  • Shaymaa Azawi
  • Kristin Mrasek
  • Thomas Liehr
  • Thomas Efferth
DOI
10.1016/j.lfs.2021.119601
ISSN
0024-3205
Zeitschrift
Life Sciences
Sprache
en
Artikelnummer
119601
Paginierung
119601 - 119601
Datum der Veröffentlichung
2021
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.lfs.2021.119601
Datum der Datenerfassung
2023
Titel
Identification of novel drug resistance mechanisms by genomic and transcriptomic profiling of glioblastoma cells with mutation-activated EGFR
Ausgabe der Zeitschrift
284

Data source: Crossref

Abstract
<h4>Aims</h4>Epidermal growth factor receptor (EGFR) is not only involved in carcinogenesis, but also in chemoresistance. We characterized U87.MGΔEGFR glioblastoma cells with constitutively active EGFR due to deletion at the ligand binding domain in terms of gene expression profiling and chromosomal aberrations. Wild-type U87.MG cells served as control.<h4>Materials and methods</h4>RNA sequencing and network analyses (Ingenuity Pathway Analysis) were performed to identify novel drug resistance mechanisms related to expression of mutation activated EGFR. Chromosomal aberrations were characterized by multicolor fluorescence in situ hybridization (mFISH) and array comparative genomic hybridization (aCGH).<h4>Key findings</h4>U87.MGΔEGFR cells presented much more chromosomal aberrations, amplifications and deletions than wild-type U87.MG cells. Both cell lines were near-triploid. Numerous genes were overexpressed in U87.MGΔEGFR cells, some of which have been already linked to drug resistance. PXDN, which is associated with epithelial mesenchymal transition, was the most upregulated gene (901.8-fold). TENM1 was 331.6-fold upregulated, and it was previously reported to modulate neural development. EGFR-AS1 (161.2-fold upregulated) has been reported to increase the EGFR mRNA stability and its expression - in accordance with that of EGFR - was upregulated (85.5-fold). In addition to well-known resistance genes, numerous novel genes and genomic aberrations were identified. ANGPT2 upregulation and CPM downregulation were validated by Western blotting.<h4>Significance</h4>Transcriptomics and genomics analyses in U87.MGΔEGFR cells unraveled a range of novel drug resistance mechanisms including apoptosis, DNA repair, ferroptosis, glutathione related gene activities, heat shock, oxidative stress, transcription factor activities, which may have important implications for future treatment strategies.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
Autoren
  • Onat Kadioglu
  • Mohamed EM Saeed
  • Nuha Mahmoud
  • Shaymaa Azawi
  • Kristin Mrasek
  • Thomas Liehr
  • Thomas Efferth
DOI
10.1016/j.lfs.2021.119601
eISSN
1879-0631
Externe Identifier
  • PubMed Identifier: 33991550
Funding acknowledgements
  • Johannes Gutenberg-Universität Mainz:
Open access
false
ISSN
0024-3205
Zeitschrift
Life sciences
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Glioblastoma
  • Brain Neoplasms
  • Chromosome Aberrations
  • Gene Expression Profiling
  • Genomics
  • Signal Transduction
  • Metaphase
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Up-Regulation
  • Drug Resistance, Neoplasm
  • Mutation
  • Gene Regulatory Networks
  • Transcriptome
  • Protein Interaction Maps
  • ErbB Receptors
Sprache
eng
Medium
Print-Electronic
Online publication date
2021
Paginierung
119601
Datum der Veröffentlichung
2021
Status
Published
Datum der Datenerfassung
2021
Titel
Identification of novel drug resistance mechanisms by genomic and transcriptomic profiling of glioblastoma cells with mutation-activated EGFR.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
284

Data source: Europe PubMed Central

Abstract
AIMS: Epidermal growth factor receptor (EGFR) is not only involved in carcinogenesis, but also in chemoresistance. We characterized U87.MGΔEGFR glioblastoma cells with constitutively active EGFR due to deletion at the ligand binding domain in terms of gene expression profiling and chromosomal aberrations. Wild-type U87.MG cells served as control. MATERIALS AND METHODS: RNA sequencing and network analyses (Ingenuity Pathway Analysis) were performed to identify novel drug resistance mechanisms related to expression of mutation activated EGFR. Chromosomal aberrations were characterized by multicolor fluorescence in situ hybridization (mFISH) and array comparative genomic hybridization (aCGH). KEY FINDINGS: U87.MGΔEGFR cells presented much more chromosomal aberrations, amplifications and deletions than wild-type U87.MG cells. Both cell lines were near-triploid. Numerous genes were overexpressed in U87.MGΔEGFR cells, some of which have been already linked to drug resistance. PXDN, which is associated with epithelial mesenchymal transition, was the most upregulated gene (901.8-fold). TENM1 was 331.6-fold upregulated, and it was previously reported to modulate neural development. EGFR-AS1 (161.2-fold upregulated) has been reported to increase the EGFR mRNA stability and its expression - in accordance with that of EGFR - was upregulated (85.5-fold). In addition to well-known resistance genes, numerous novel genes and genomic aberrations were identified. ANGPT2 upregulation and CPM downregulation were validated by Western blotting. SIGNIFICANCE: Transcriptomics and genomics analyses in U87.MGΔEGFR cells unraveled a range of novel drug resistance mechanisms including apoptosis, DNA repair, ferroptosis, glutathione related gene activities, heat shock, oxidative stress, transcription factor activities, which may have important implications for future treatment strategies.
Date of acceptance
2021
Autoren
  • Onat Kadioglu
  • Mohamed EM Saeed
  • Nuha Mahmoud
  • Shaymaa Azawi
  • Kristin Mrasek
  • Thomas Liehr
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/33991550
DOI
10.1016/j.lfs.2021.119601
eISSN
1879-0631
Zeitschrift
Life Sci
Schlüsselwörter
  • Cancer
  • Chromosomal aberrations
  • Drug resistance
  • Oncogenes
  • Transcriptomics
  • Brain Neoplasms
  • Cell Line, Tumor
  • Chromosome Aberrations
  • Down-Regulation
  • Drug Resistance, Neoplasm
  • ErbB Receptors
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Genomics
  • Glioblastoma
  • Humans
  • Metaphase
  • Mutation
  • Protein Interaction Maps
  • Signal Transduction
  • Transcriptome
  • Up-Regulation
Sprache
eng
Country
Netherlands
Paginierung
119601
PII
S0024-3205(21)00587-7
Datum der Veröffentlichung
2021
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2021
Titel
Identification of novel drug resistance mechanisms by genomic and transcriptomic profiling of glioblastoma cells with mutation-activated EGFR.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
284

Data source: PubMed

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