title: Identification of drugs that restore primary cilium expression in cancer cells.
abstract: The development of cancer is often accompanied by a loss of the primary cilium, a microtubule-based cellular protrusion that functions as a cellular antenna and that puts a break on cell proliferation. Hence, restoration of the primary cilium in cancer cells may represent a novel promising approach to attenuate tumor growth. Using a high content analysis-based approach we screened a library of clinically evaluated compounds and marketed drugs for their ability to restore primary cilium expression in pancreatic ductal cancer cells. A diverse set of 118 compounds stimulating cilium expression was identified. These included glucocorticoids, fibrates and other nuclear receptor modulators, neurotransmitter regulators, ion channel modulators, tyrosine kinase inhibitors, DNA gyrase/topoisomerase inhibitors, antibacterial compounds, protein inhibitors, microtubule modulators, and COX inhibitors. Certain compounds also dramatically affected the length of the cilium. For a selection of compounds (Clofibrate, Gefitinib, Sirolimus, Imexon and Dexamethasone) their ability to restore ciliogenesis was confirmed in a panel of human cancer cell line models representing different cancer types (pancreas, lung, kidney, breast). Most compounds attenuated cell proliferation, at least in part through induction of the primary cilium, as demonstrated by cilium removal using chloral hydrate. These findings reveal that several commonly used drugs restore ciliogenesis in cancer cells, and warrant further investigation of their antineoplastic properties.
authors: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, 3000 Leuven, Belgium.
authors: Niamat Ali
authors: NA
authors: Khan
authors: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, 3000 Leuven, Belgium.
authors: Nicolas
authors: N
authors: Willemarck
authors: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, 3000 Leuven, Belgium.
authors: Ali
authors: A
authors: Talebi
authors: Cistim Leuven vzw, Bioincubator 2, 3001 Leuven, Belgium.
authors: Arnaud
authors: A
authors: Marchand
authors: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, 3000 Leuven, Belgium.
authors: Maria Mercedes
authors: MM
authors: Binda
authors: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, 3000 Leuven, Belgium.
authors: Jonas
authors: J
authors: Dehairs
authors: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, 3000 Leuven, Belgium.
authors: Natalia
authors: N
authors: Rueda-Rincon
authors: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, 3000 Leuven, Belgium.
authors: Veerle W
authors: VW
authors: Daniels
authors: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, 3000 Leuven, Belgium.
authors: Muralidhararao
authors: M
authors: Bagadi
authors: European Molecular Biology Laboratory (EMBL), Grenoble Outstation and Unit of Virus Host-Cell Interactions (UVHCI), UJF-EMBL-CNRS, CS 90181, France.
authors: Deepak Balaji
authors: DB
authors: Thimiri Govinda Raj
authors: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, 3000 Leuven, Belgium.
authors: Frank
authors: F
authors: Vanderhoydonc
authors: VIB Bio Imaging Core and Center for the Biology of Disease, 3000 Leuven, Belgium.|KU Leuven - University of Leuven, Center for Human Genetics, 3000 Leuven, Belgium.
authors: Sebastian
authors: S
authors: Munck
authors: Cistim Leuven vzw, Bioincubator 2, 3001 Leuven, Belgium.|Centre for Drug Design and Discovery (CD3) KU Leuven R & D, Bioincubator 2, 3001 Leuven, Belgium.
authors: Patrick
authors: P
authors: Chaltin
authors: KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, 3000 Leuven, Belgium.
authors: Johannes V
authors: JV
authors: Swinnen
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000145:classification / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002923:Cilia / Q000187:drug effects* / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D000077156:Gefitinib; D006801:Humans; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology; D015203:Reproducibility of Results
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077156:Gefitinib
keywords: cancer; cilium; high content analysis; small molecules; therapeutics