title: 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(+)-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.affiliation: Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hamm
authors.affiliation: Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
authors.forename: Maen
authors.initials: M
authors.lastname: Zeino
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, Saarbrücken, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Frewert
authors.affiliation: Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address: efferth@uni-mainz.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis* / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D018942:Macrolides / Q000633:toxicity*; D013844:Thiazoles / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D018942:Macrolides; D013844:Thiazoles; C519728:archazolid B; D002784:Cholesterol
keywords: Archazolid B; Cholesterol; Glioblastoma multiforme; SREBP; Statins; V-ATPase