Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion

Publication type:
Journal article
Metadata:
Autoren
  • Onat Kadioglu
  • Mohamed 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:000613057300001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1007/s00204-021-02979-4
eISSN
1432-0738
Externe Identifier
  • Clarivate Analytics Document Solution ID: QM1DA
  • PubMed Identifier: 33515271
ISSN
0340-5761
Ausgabe der Veröffentlichung
3
Zeitschrift
ARCHIVES OF TOXICOLOGY
Schlüsselwörter
  • Cancer
  • Chromosomal aberrations
  • Drug resistance
  • Genomic instability
  • Loss-of-function
  • Transcriptomics
  • Tumor suppressor
Paginierung
959 - 974
Datum der Veröffentlichung
2021
Status
Published
Titel
Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion
Sub types
  • Article
Ausgabe der Zeitschrift
95

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:title>Abstract</jats:title><jats:p>TP53 (p53) is a pivotal player in tumor suppression with fifty percent of all invasive tumors displaying mutations in the <jats:italic>TP53</jats:italic> gene. In the present study, we characterized colon cancer cells (HCT116 <jats:italic>p53</jats:italic> <jats:sup><jats:italic>−/−</jats:italic></jats:sup>) with <jats:italic>TP53</jats:italic> deletion, a sub-line derived from HCT116-<jats:italic>p53</jats:italic> <jats:sup>+<jats:italic>/</jats:italic>+</jats:sup> cells. RNA sequencing and network analyses were performed to identify novel drug resistance mechanisms. Chromosomal aberrations were identified by multicolor fluorescence in situ hybridization (mFISH) and array comparative genomic hybridization (aCGH). Numerous genes were overexpressed in HCT116 <jats:italic>p53</jats:italic> <jats:sup><jats:italic>−/−</jats:italic></jats:sup> cells: <jats:italic>RND3/RhoE</jats:italic> (235.6-fold up-regulated), <jats:italic>DCLK1</jats:italic> (60.2-fold up-regulated), <jats:italic>LBH</jats:italic> (31.9-fold up-regulated), <jats:italic>MYB</jats:italic> (28.9-fold up-regulated), <jats:italic>TACSTD2</jats:italic> (110.1-fold down-regulated), <jats:italic>NRIP1</jats:italic> (81.5-fold down-regulated) and <jats:italic>HLA-DMB</jats:italic> (69.7-fold down-regulated) are among the identified genes with potential influence on multidrug resistance (MDR) and they are associated with cancer progression and tumorigenesis, according to previously published studies. Probably due to <jats:italic>TP53</jats:italic> deletion, disturbances in DNA repair and apoptosis are leading to aberrancies in cellular and organismal organization, ultimately increasing tumorigenesis and cancer progression potential. With NFκB, PI3K and HSP70, being at the center of merged protein network, and TH1-2 pathways, being among the influenced pathways, it can be speculated that the inflammatory pathway contributes to a resistance phenotype together with cell cycle regulation and heat-shock response. HCT116-<jats:italic>p53</jats:italic> <jats:sup><jats:italic>−/−</jats:italic></jats:sup> cells have more chromosomal aberrations, gains and losses in copy numbers than HCT116-<jats:italic>p53</jats:italic> <jats:sup>+<jats:italic>/</jats:italic>+</jats:sup> cells. In conclusion, numerous genomic aberrations, which might be associated with yet unknown drug resistance mechanisms, were identified. This may have important implications for future treatment strategies.</jats:p>
Autoren
  • Onat Kadioglu
  • Mohamed Saeed
  • Nuha Mahmoud
  • Shaymaa Azawi
  • Kristin Mrasek
  • Thomas Liehr
  • Thomas Efferth
DOI
10.1007/s00204-021-02979-4
eISSN
1432-0738
ISSN
0340-5761
Ausgabe der Veröffentlichung
3
Zeitschrift
Archives of Toxicology
Sprache
en
Online publication date
2021
Paginierung
959 - 974
Datum der Veröffentlichung
2021
Status
Published
Herausgeber
Springer Science and Business Media LLC
Herausgeber URL
http://dx.doi.org/10.1007/s00204-021-02979-4
Datum der Datenerfassung
2021
Titel
Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion
Ausgabe der Zeitschrift
95

Data source: Crossref

Abstract
TP53 (p53) is a pivotal player in tumor suppression with fifty percent of all invasive tumors displaying mutations in the TP53 gene. In the present study, we characterized colon cancer cells (HCT116 p53 <sup>-/-</sup>) with TP53 deletion, a sub-line derived from HCT116-p53 <sup>+/+</sup> cells. RNA sequencing and network analyses were performed to identify novel drug resistance mechanisms. Chromosomal aberrations were identified by multicolor fluorescence in situ hybridization (mFISH) and array comparative genomic hybridization (aCGH). Numerous genes were overexpressed in HCT116 p53 <sup>-/-</sup> cells: RND3/RhoE (235.6-fold up-regulated), DCLK1 (60.2-fold up-regulated), LBH (31.9-fold up-regulated), MYB (28.9-fold up-regulated), TACSTD2 (110.1-fold down-regulated), NRIP1 (81.5-fold down-regulated) and HLA-DMB (69.7-fold down-regulated) are among the identified genes with potential influence on multidrug resistance (MDR) and they are associated with cancer progression and tumorigenesis, according to previously published studies. Probably due to TP53 deletion, disturbances in DNA repair and apoptosis are leading to aberrancies in cellular and organismal organization, ultimately increasing tumorigenesis and cancer progression potential. With NFκB, PI3K and HSP70, being at the center of merged protein network, and TH1-2 pathways, being among the influenced pathways, it can be speculated that the inflammatory pathway contributes to a resistance phenotype together with cell cycle regulation and heat-shock response. HCT116-p53 <sup>-/-</sup> cells have more chromosomal aberrations, gains and losses in copy numbers than HCT116-p53 <sup>+/+</sup> cells. In conclusion, numerous genomic aberrations, which might be associated with yet unknown drug resistance mechanisms, were identified. This 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 Saeed
  • Nuha Mahmoud
  • Shaymaa Azawi
  • Kristin Mrasek
  • Thomas Liehr
  • Thomas Efferth
DOI
10.1007/s00204-021-02979-4
eISSN
1432-0738
Externe Identifier
  • PubMed Identifier: 33515271
  • PubMed Central ID: PMC7904745
Funding acknowledgements
  • Projekt DEAL:
Open access
true
ISSN
0340-5761
Ausgabe der Veröffentlichung
3
Zeitschrift
Archives of toxicology
Schlüsselwörter
  • HCT116 Cells
  • Humans
  • Colonic Neoplasms
  • Chromosome Aberrations
  • Disease Progression
  • Antineoplastic Agents
  • In Situ Hybridization, Fluorescence
  • Gene Expression Profiling
  • Sequence Analysis, RNA
  • Drug Resistance, Multiple
  • Apoptosis
  • DNA Repair
  • Gene Expression Regulation, Neoplastic
  • Gene Deletion
  • Drug Resistance, Neoplasm
  • Mutation
  • Tumor Suppressor Protein p53
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations
Sprache
eng
Medium
Print-Electronic
Online publication date
2021
Open access status
Open Access
Paginierung
959 - 974
Datum der Veröffentlichung
2021
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2021
Titel
Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
95

Files

https://link.springer.com/content/pdf/10.1007/s00204-021-02979-4.pdf https://europepmc.org/articles/PMC7904745?pdf=render

Data source: Europe PubMed Central

Abstract
TP53 (p53) is a pivotal player in tumor suppression with fifty percent of all invasive tumors displaying mutations in the TP53 gene. In the present study, we characterized colon cancer cells (HCT116 p53 -/-) with TP53 deletion, a sub-line derived from HCT116-p53 +/+ cells. RNA sequencing and network analyses were performed to identify novel drug resistance mechanisms. Chromosomal aberrations were identified by multicolor fluorescence in situ hybridization (mFISH) and array comparative genomic hybridization (aCGH). Numerous genes were overexpressed in HCT116 p53 -/- cells: RND3/RhoE (235.6-fold up-regulated), DCLK1 (60.2-fold up-regulated), LBH (31.9-fold up-regulated), MYB (28.9-fold up-regulated), TACSTD2 (110.1-fold down-regulated), NRIP1 (81.5-fold down-regulated) and HLA-DMB (69.7-fold down-regulated) are among the identified genes with potential influence on multidrug resistance (MDR) and they are associated with cancer progression and tumorigenesis, according to previously published studies. Probably due to TP53 deletion, disturbances in DNA repair and apoptosis are leading to aberrancies in cellular and organismal organization, ultimately increasing tumorigenesis and cancer progression potential. With NFκB, PI3K and HSP70, being at the center of merged protein network, and TH1-2 pathways, being among the influenced pathways, it can be speculated that the inflammatory pathway contributes to a resistance phenotype together with cell cycle regulation and heat-shock response. HCT116-p53 -/- cells have more chromosomal aberrations, gains and losses in copy numbers than HCT116-p53 +/+ cells. In conclusion, numerous genomic aberrations, which might be associated with yet unknown drug resistance mechanisms, were identified. This may have important implications for future treatment strategies.
Date of acceptance
2021
Autoren
  • Onat Kadioglu
  • Mohamed Saeed
  • Nuha Mahmoud
  • Shaymaa Azawi
  • Kristin Mrasek
  • Thomas Liehr
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/33515271
DOI
10.1007/s00204-021-02979-4
eISSN
1432-0738
Externe Identifier
  • PubMed Central ID: PMC7904745
Ausgabe der Veröffentlichung
3
Zeitschrift
Arch Toxicol
Schlüsselwörter
  • Cancer
  • Chromosomal aberrations
  • Drug resistance
  • Genomic instability
  • Loss-of-function
  • Transcriptomics
  • Tumor suppressor
  • Antineoplastic Agents
  • Apoptosis
  • Chromosome Aberrations
  • Colonic Neoplasms
  • Comparative Genomic Hybridization
  • DNA Copy Number Variations
  • DNA Repair
  • Disease Progression
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Humans
  • In Situ Hybridization, Fluorescence
  • Mutation
  • Sequence Analysis, RNA
  • Tumor Suppressor Protein p53
Sprache
eng
Country
Germany
Paginierung
959 - 974
PII
10.1007/s00204-021-02979-4
Datum der Veröffentlichung
2021
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2021
Titel
Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
95

Data source: PubMed

Author's licence
CC-BY
Autoren
  • Onat Kadioglu
  • Mohamed Saeed
  • Nuha Mahmoud
  • Shaymaa Azawi
  • Kristin Mrasek
  • Thomas Liehr
  • Thomas Efferth
Hosting institution
Universitätsbibliothek Mainz
Sammlungen
  • JGU-Publikationen
Resource version
Published version
DOI
10.1007/s00204-021-02979-4
File(s) embargoed
false
Open access
true
ISSN
1432-0738
Zeitschrift
Archives of toxicology
Schlüsselwörter
  • 610 Medizin
  • 610 Medical sciences
Sprache
eng
Open access status
Open Access
Paginierung
959 - 974
Datum der Veröffentlichung
2021
Public URL
https://openscience.ub.uni-mainz.de/handle/20.500.12030/7291
Herausgeber
Springer
Datum der Datenerfassung
2022
Datum, an dem der Datensatz öffentlich gemacht wurde
2022
Zugang
Public
Titel
Identification of potential novel drug resistance mechanisms by genomic and transcriptomic profiling of colon cancer cells with p53 deletion
Ausgabe der Zeitschrift
95

Files

identification_of_potential_n-20220701123610800.pdf

Data source: OPENSCIENCE.UB

Beziehungen:
Property of

Tools