title: β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids.
abstract: Cancer cells form three-dimensional (3D) multicellular aggregates (or spheroids) under non-adherent culture conditions. In ovarian cancer (OC), spheroids serve as a vehicle for cancer cell dissemination in the peritoneal cavity, protecting cells from environmental stress-induced anoikis. To identify new targetable molecules in OC spheroids, we investigated gene expression profiles and networks upregulated in 3D vs traditional monolayer culture conditions. We identified ALDH1A1, a cancer stem cell marker as being overexpressed in OC spheroids and directly connected to key elements of the β-catenin pathway. β-Catenin function and ALDH1A1 expression were increased in OC spheroids vs monolayers and in successive spheroid generations, suggesting that 3D aggregates are enriched in cells with stem cell characteristics. β-Catenin knockdown decreased ALDH1A1 expression levels and β-catenin co-immunoprecipitated with the ALDH1A1 promoter, suggesting that ALDH1A1 is a direct β-catenin target. Both short interfering RNA-mediated β-catenin knockdown and A37 ((ethyl-2-((4-oxo-3-(3-(pryrrolidin-1-yl)propyl)-3,4-dihydrobenzo [4,5]thioeno [3,2-d]pyrimidin-2-yl)thio)acetate)), a novel ALDH1A1 small-molecule enzymatic inhibitor described here for the first time, disrupted OC spheroid formation and cell viability (P<0.001). β-Catenin knockdown blocked tumor growth and peritoneal metastasis in an OC xenograft model. These data strongly support the role of β-catenin-regulated ALDH1A1 in the maintenance of OC spheroids and propose new ALDH1A1 inhibitors targeting this cell population.
authors: Department of Medicine, Indianapolis, IN, USA.
authors: S
authors: S
authors: Condello
authors: Department of Biochemistry and Molecular Biology, Indianapolis, IN, USA.
authors: C A
authors: CA
authors: Morgan
authors: University of Virginia Medical School, Indianapolis, IN, USA.
authors: S
authors: S
authors: Nagdas
authors: Department of Medicine, Indianapolis, IN, USA.
authors: L
authors: L
authors: Cao
authors: College of Veterinary Medicine Purdue University, Indianapolis, IN, USA.
authors: J
authors: J
authors: Turek
authors: 1] Department of Biochemistry and Molecular Biology, Indianapolis, IN, USA [2] Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.
authors: T D
authors: TD
authors: Hurley
authors: 1] Department of Medicine, Indianapolis, IN, USA [2] Department of Biochemistry and Molecular Biology, Indianapolis, IN, USA [3] Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA [4] VA Roudebush Hospital, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: D
authors: D
authors: Matei
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D050697:Retinal Dehydrogenase; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D051176:beta Catenin; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase