Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B
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{sup +}-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.
- Authors:
-
- Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz (Germany)
- Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken (Germany)
- Publication Date:
- OSTI Identifier:
- 22439911
- Resource Type:
- Journal Article
- Journal Name:
- Toxicology and Applied Pharmacology
- Additional Journal Information:
- Journal Volume: 281; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; BIOSYNTHESIS; BRAIN; CHOLESTEROL; CONCENTRATION RATIO; DRUGS; ENZYMES; GENES; GLIOMAS; GROWTH FACTORS; HAMSTERS; HOMEOSTASIS; HYDROGEN IONS 1 PLUS; MEMBRANES; MICROARRAY TECHNOLOGY; MUTANTS; MUTATIONS; OVARIES; RECEPTORS; TOXICITY
Citation Formats
Hamm, Rebecca, Zeino, Maen, Frewert, Simon, and Efferth, Thomas. Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B. United States: N. p., 2014.
Web. doi:10.1016/J.TAAP.2014.08.033.
Hamm, Rebecca, Zeino, Maen, Frewert, Simon, & Efferth, Thomas. Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B. United States. https://doi.org/10.1016/J.TAAP.2014.08.033
Hamm, Rebecca, Zeino, Maen, Frewert, Simon, and Efferth, Thomas. 2014.
"Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B". United States. https://doi.org/10.1016/J.TAAP.2014.08.033.
@article{osti_22439911,
title = {Up-regulation of cholesterol associated genes as novel resistance mechanism in glioblastoma cells in response to archazolid B},
author = {Hamm, Rebecca and Zeino, Maen and Frewert, Simon and Efferth, Thomas},
abstractNote = {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{sup +}-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.},
doi = {10.1016/J.TAAP.2014.08.033},
url = {https://www.osti.gov/biblio/22439911},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1,
volume = 281,
place = {United States},
year = {Sat Nov 15 00:00:00 EST 2014},
month = {Sat Nov 15 00:00:00 EST 2014}
}