Induction of cholesterol biosynthesis by archazolid B in T24 bladder cancer cells

Publication type:
Journal article
Metadata:
Autoren
  • R Hamm
  • Y-R Chen
  • Ean-Jeong Seo
  • Maen Zeino
  • Ching-Fen Wu
  • R Mueller
  • N-S Yang
  • T Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000340231300003&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.bcp.2014.06.018
eISSN
1873-2968
Externe Identifier
  • Clarivate Analytics Document Solution ID: AM9WI
  • PubMed Identifier: 24976507
ISSN
0006-2952
Ausgabe der Veröffentlichung
1
Zeitschrift
BIOCHEMICAL PHARMACOLOGY
Schlüsselwörter
  • Archazolid B
  • Cholesterol biosynthesis
  • Fluvastatin
  • LDL uptake
  • SREBP
  • V-ATPase inhibition
Paginierung
18 - 30
Datum der Veröffentlichung
2014
Status
Published
Titel
Induction of cholesterol biosynthesis by archazolid B in T24 bladder cancer cells
Sub types
  • Article
Ausgabe der Zeitschrift
91

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • R Hamm
  • Y-R Chen
  • Ean-Jeong Seo
  • Maen Zeino
  • Ching-Fen Wu
  • R Müller
  • N-S Yang
  • T Efferth
DOI
10.1016/j.bcp.2014.06.018
ISSN
0006-2952
Ausgabe der Veröffentlichung
1
Zeitschrift
Biochemical Pharmacology
Sprache
en
Paginierung
18 - 30
Datum der Veröffentlichung
2014
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.bcp.2014.06.018
Datum der Datenerfassung
2022
Titel
Induction of cholesterol biosynthesis by archazolid B in T24 bladder cancer cells
Ausgabe der Zeitschrift
91

Data source: Crossref

Abstract
<h4>Background</h4>Resistance of cancer cells towards chemotherapeutics represents a major cause of therapy failure. The objective of our study was to evaluate cellular defense strategies in response to the novel vacuolar H(+)-ATPase inhibitor, archazolid B.<h4>Experimental approach</h4>The effects of archazolid B on T24 bladder carcinoma cells were investigated by combining "omics" technologies (transcriptomics (mRNA and miRNA) and proteomics). Free cholesterol distribution was determined by filipin staining using flow cytometry and fluorescence microscopy. Flow cytometry was performed for LDLR surface expression studies. Uptake of LDL cholesterol was visualized by confocal microscopy. SREBP activation was determined performing Western Blotting. The efficiency of archazolid B/fluvastatin combination was tested by cytotoxicity assays.<h4>Results</h4>Archazolid B led to accumulation of free cholesterol within intracellular compartments and drastic disturbances in cholesterol homeostasis resulting in activation of SREBP-2 (sterol regulatory element-binding protein 2) and up-regulation of target genes including HMGCR (HMG-CoA reductase), the key enzyme of cholesterol biosynthesis. LDLR surface expression was reduced and LDL uptake was completely inhibited after 24h, indicating newly synthesized cholesterol to be the main source of cholesterol in archazolid B treated cells. By combining archazolid B with the HMGCR inhibitor fluvastatin, cholesterol was reduced and cell viability decreased by about 20% compared to archazolid B treatment alone.<h4>Conclusions</h4>Our study revealed cholesterol biosynthesis as an important resistance mechanism in T24 cells after archazolid B treatment. The combination of archazolid B with statins may be an attractive strategy to potentiate archazolid B induced cell killing by affecting cholesterol biosynthesis.
Addresses
  • Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Autoren
  • R Hamm
  • Y-R Chen
  • Ean-Jeong Seo
  • Maen Zeino
  • Ching-Fen Wu
  • R Müller
  • N-S Yang
  • T Efferth
  • T Efferth
DOI
10.1016/j.bcp.2014.06.018
eISSN
1873-2968
Externe Identifier
  • PubMed Identifier: 24976507
Open access
false
ISSN
0006-2952
Ausgabe der Veröffentlichung
1
Zeitschrift
Biochemical pharmacology
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Macrolides
  • Thiazoles
  • Indoles
  • Cholesterol
  • Fatty Acids, Monounsaturated
  • Lipoproteins, LDL
  • Receptors, LDL
  • MicroRNAs
  • Reproducibility of Results
  • Cell Survival
  • Endocytosis
  • Gene Expression Regulation, Neoplastic
  • Drug Resistance, Neoplasm
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Urinary Bladder Neoplasms
  • Real-Time Polymerase Chain Reaction
  • Fluvastatin
Sprache
eng
Medium
Print-Electronic
Online publication date
2014
Paginierung
18 - 30
Datum der Veröffentlichung
2014
Status
Published
Datum der Datenerfassung
2014
Titel
Induction of cholesterol biosynthesis by archazolid B in T24 bladder cancer cells.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
91

Data source: Europe PubMed Central

Abstract
BACKGROUND: Resistance of cancer cells towards chemotherapeutics represents a major cause of therapy failure. The objective of our study was to evaluate cellular defense strategies in response to the novel vacuolar H(+)-ATPase inhibitor, archazolid B. EXPERIMENTAL APPROACH: The effects of archazolid B on T24 bladder carcinoma cells were investigated by combining "omics" technologies (transcriptomics (mRNA and miRNA) and proteomics). Free cholesterol distribution was determined by filipin staining using flow cytometry and fluorescence microscopy. Flow cytometry was performed for LDLR surface expression studies. Uptake of LDL cholesterol was visualized by confocal microscopy. SREBP activation was determined performing Western Blotting. The efficiency of archazolid B/fluvastatin combination was tested by cytotoxicity assays. RESULTS: Archazolid B led to accumulation of free cholesterol within intracellular compartments and drastic disturbances in cholesterol homeostasis resulting in activation of SREBP-2 (sterol regulatory element-binding protein 2) and up-regulation of target genes including HMGCR (HMG-CoA reductase), the key enzyme of cholesterol biosynthesis. LDLR surface expression was reduced and LDL uptake was completely inhibited after 24h, indicating newly synthesized cholesterol to be the main source of cholesterol in archazolid B treated cells. By combining archazolid B with the HMGCR inhibitor fluvastatin, cholesterol was reduced and cell viability decreased by about 20% compared to archazolid B treatment alone. CONCLUSIONS: Our study revealed cholesterol biosynthesis as an important resistance mechanism in T24 cells after archazolid B treatment. The combination of archazolid B with statins may be an attractive strategy to potentiate archazolid B induced cell killing by affecting cholesterol biosynthesis.
Date of acceptance
2014
Autoren
  • R Hamm
  • Y-R Chen
  • Ean-Jeong Seo
  • Maen Zeino
  • Ching-Fen Wu
  • R Müller
  • N-S Yang
  • T Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/24976507
DOI
10.1016/j.bcp.2014.06.018
eISSN
1873-2968
Ausgabe der Veröffentlichung
1
Zeitschrift
Biochem Pharmacol
Schlüsselwörter
  • Archazolid B
  • Cholesterol biosynthesis
  • Fluvastatin
  • LDL uptake
  • SREBP
  • V-ATPase inhibition.
  • Cell Line, Tumor
  • Cell Survival
  • Cholesterol
  • Drug Resistance, Neoplasm
  • Endocytosis
  • Fatty Acids, Monounsaturated
  • Fluvastatin
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Indoles
  • Lipoproteins, LDL
  • Macrolides
  • MicroRNAs
  • Real-Time Polymerase Chain Reaction
  • Receptors, LDL
  • Reproducibility of Results
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Thiazoles
  • Urinary Bladder Neoplasms
Sprache
eng
Country
England
Paginierung
18 - 30
PII
S0006-2952(14)00361-X
Datum der Veröffentlichung
2014
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2014
Titel
Induction of cholesterol biosynthesis by archazolid B in T24 bladder cancer cells.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
91

Data source: PubMed

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