Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B

Autoren

Rebecca Hamm
Maen Zeino
Simon Frewert
Thomas Efferth

DOI

10.1016/j.taap.2014.08.033

ISSN

0041-008X

Ausgabe der Veröffentlichung

1

Zeitschrift

Toxicology and Applied Pharmacology

Sprache

en

Paginierung

78 - 86

Datum der Veröffentlichung

2014

Status

Published

Herausgeber

Elsevier BV

Herausgeber URL

http://dx.doi.org/10.1016/j.taap.2014.08.033

Datum der Datenerfassung

2021

Titel

Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B

Ausgabe der Zeitschrift

281

Data source: Crossref

Abstract

Treatment of glioblastoma multiforme (GBM), the most common and aggressive lethal brain tumor, represents a great challenge. Despite decades of research, the survival prognosis of GBM patients is unfavorable and more effective therapeutics are sorely required. Archazolid B, a potent vacuolar H(+)-ATPase inhibitor influencing cellular pH values, is a promising new compound exerting cytotoxicity in the nanomolar range on wild-type U87MG glioblastoma cells and U87MG.∆EGFR cells transfected with a mutant epidermal growth factor receptor (EGFR) gene. Gene expression profiling using microarray technology showed that archazolid B caused drastic disturbances in cholesterol homeostasis. Cholesterol, a main component of cellular membranes, is known to be essential for GBM growth and cells bearing EGFRvIII mutation are highly dependent on exogenous cholesterol. Archazolid B caused excessive accumulation of free cholesterol within intracellular compartments thus depleting cellular cholesterol and leading to up-regulation of SREBP targeted genes, including LDLR and HMGCR, the key enzyme of cholesterol biosynthesis. This cholesterol response is considered to be a novel resistance mechanism induced by archazolid B. We surmise that re-elevation of cholesterol levels in archazolid B treated cells may be mediated by newly synthesized cholesterol, since the drug leads to endosomal/lysosomal malfunction and cholesterol accumulation.

Addresses

Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.

Autoren

Rebecca Hamm
Maen Zeino
Simon Frewert
Thomas Efferth
Thomas Efferth

DOI

10.1016/j.taap.2014.08.033

eISSN

1096-0333

Externe Identifier

PubMed Identifier: 25218289

Funding acknowledgements

Microarray Core Facility of DKFZ (Heidelberg, Germany):
IMB Core Facility Cytometry (Mainz, Germany):

Open access

false

ISSN

0041-008X

Ausgabe der Veröffentlichung

1

Zeitschrift

Toxicology and applied pharmacology

Schlüsselwörter

Cell Line, Tumor
Humans
Glioblastoma
Macrolides
Thiazoles
Cholesterol
Up-Regulation
Drug Resistance, Neoplasm

Sprache

eng

Medium

Print-Electronic

Online publication date

2014

Paginierung

78 - 86

Datum der Veröffentlichung

2014

Status

Published

Datum der Datenerfassung

2014

Titel

Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B.

Sub types

Research Support, Non-U.S. Gov't
Journal Article

Ausgabe der Zeitschrift

281

Data source: Europe PubMed Central

Abstract

Treatment of glioblastoma multiforme (GBM), the most common and aggressive lethal brain tumor, represents a great challenge. Despite decades of research, the survival prognosis of GBM patients is unfavorable and more effective therapeutics are sorely required. Archazolid B, a potent vacuolar H(+)-ATPase inhibitor influencing cellular pH values, is a promising new compound exerting cytotoxicity in the nanomolar range on wild-type U87MG glioblastoma cells and U87MG.∆EGFR cells transfected with a mutant epidermal growth factor receptor (EGFR) gene. Gene expression profiling using microarray technology showed that archazolid B caused drastic disturbances in cholesterol homeostasis. Cholesterol, a main component of cellular membranes, is known to be essential for GBM growth and cells bearing EGFRvIII mutation are highly dependent on exogenous cholesterol. Archazolid B caused excessive accumulation of free cholesterol within intracellular compartments thus depleting cellular cholesterol and leading to up-regulation of SREBP targeted genes, including LDLR and HMGCR, the key enzyme of cholesterol biosynthesis. This cholesterol response is considered to be a novel resistance mechanism induced by archazolid B. We surmise that re-elevation of cholesterol levels in archazolid B treated cells may be mediated by newly synthesized cholesterol, since the drug leads to endosomal/lysosomal malfunction and cholesterol accumulation.

Date of acceptance

2014

Autoren

Rebecca Hamm
Maen Zeino
Simon Frewert
Thomas Efferth

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/25218289

DOI

10.1016/j.taap.2014.08.033

eISSN

1096-0333

Ausgabe der Veröffentlichung

1

Zeitschrift

Toxicol Appl Pharmacol

Schlüsselwörter

Archazolid B
Cholesterol
Glioblastoma multiforme
SREBP
Statins
V-ATPase
Cell Line, Tumor
Cholesterol
Drug Resistance, Neoplasm
Glioblastoma
Humans
Macrolides
Thiazoles
Up-Regulation

Sprache

eng

Country

United States

Paginierung

78 - 86

PII

S0041-008X(14)00325-1

Datum der Veröffentlichung

2014

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2017

Titel

Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B.

Sub types

Journal Article
Research Support, Non-U.S. Gov't

Ausgabe der Zeitschrift

281

Data source: PubMed

Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B

Tools