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Induction of cholesterol biosynthesis by archazolid B in T24 bladder cancer cells. 2014

R Hamm, and Y-R Chen, and Ean-Jeong Seo, and Maen Zeino, and Ching-Fen Wu, and R Müller, and N-S Yang, and T Efferth
Institute of Pharmacy and Biochemistry, Department of Pharmaceutical Biology, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.

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. METHODS 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.

UI MeSH Term Description Entries
D007211 Indoles Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
D008077 Lipoproteins, LDL A class of lipoproteins of small size (18-25 nm) and light (1.019-1.063 g/ml) particles with a core composed mainly of CHOLESTEROL ESTERS and smaller amounts of TRIGLYCERIDES. The surface monolayer consists mostly of PHOSPHOLIPIDS, a single copy of APOLIPOPROTEIN B-100, and free cholesterol molecules. The main LDL function is to transport cholesterol and cholesterol esters to extrahepatic tissues. Low-Density Lipoprotein,Low-Density Lipoproteins,beta-Lipoprotein,beta-Lipoproteins,LDL(1),LDL(2),LDL-1,LDL-2,LDL1,LDL2,Low-Density Lipoprotein 1,Low-Density Lipoprotein 2,LDL Lipoproteins,Lipoprotein, Low-Density,Lipoproteins, Low-Density,Low Density Lipoprotein,Low Density Lipoprotein 1,Low Density Lipoprotein 2,Low Density Lipoproteins,beta Lipoprotein,beta Lipoproteins
D011973 Receptors, LDL Receptors on the plasma membrane of nonhepatic cells that specifically bind LDL. The receptors are localized in specialized regions called coated pits. Hypercholesteremia is caused by an allelic genetic defect of three types: 1, receptors do not bind to LDL; 2, there is reduced binding of LDL; and 3, there is normal binding but no internalization of LDL. In consequence, entry of cholesterol esters into the cell is impaired and the intracellular feedback by cholesterol on 3-hydroxy-3-methylglutaryl CoA reductase is lacking. LDL Receptors,Lipoprotein LDL Receptors,Receptors, Low Density Lipoprotein,LDL Receptor,LDL Receptors, Lipoprotein,Low Density Lipoprotein Receptor,Low Density Lipoprotein Receptors,Receptors, Lipoprotein, LDL,Receptor, LDL,Receptors, Lipoprotein LDL
D001749 Urinary Bladder Neoplasms Tumors or cancer of the URINARY BLADDER. Bladder Cancer,Bladder Neoplasms,Cancer of Bladder,Bladder Tumors,Cancer of the Bladder,Malignant Tumor of Urinary Bladder,Neoplasms, Bladder,Urinary Bladder Cancer,Bladder Cancers,Bladder Neoplasm,Bladder Tumor,Cancer, Bladder,Cancer, Urinary Bladder,Neoplasm, Bladder,Neoplasm, Urinary Bladder,Tumor, Bladder,Tumors, Bladder,Urinary Bladder Neoplasm
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D002784 Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Epicholesterol
D004705 Endocytosis Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. ENDOSOMES play a central role in endocytosis. Endocytoses
D005229 Fatty Acids, Monounsaturated Fatty acids which are unsaturated in only one position. Monounsaturated Fatty Acid,Acid, Monounsaturated Fatty,Acids, Monounsaturated Fatty,Fatty Acid, Monounsaturated,Monounsaturated Fatty Acids
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077340 Fluvastatin An indole-heptanoic acid derivative that inhibits HMG COA REDUCTASE and is used to treat HYPERCHOLESTEROLEMIA. In contrast to other statins, it does not appear to interact with other drugs that inhibit CYP3A4. 7-(3-(4-Fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl)-3,5-dihydroxy-6-heptenoate,Fluindostatin,Fluvastatin Sodium,Fluvastatin Sodium Salt,Lescol,XU 62-320,XU 62320,XU-62320,XU 62 320,XU62320

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