β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids.

Academic Article

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

    Published In

  • Oncogene  Journal
  • Keywords

  • Aldehyde Dehydrogenase, Animals, Cell Culture Techniques, Cell Line, Tumor, Enzyme Inhibitors, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Neoplasm Transplantation, Ovarian Neoplasms, Peritoneal Neoplasms, RNA, Small Interfering, Spheroids, Cellular, Wnt Signaling Pathway, beta Catenin
  • Digital Object Identifier (doi)

    Author List

  • Condello S; Morgan CA; Nagdas S; Cao L; Turek J; Hurley TD; Matei D
  • Start Page

  • 2297
  • End Page

  • 2308
  • Volume

  • 34
  • Issue

  • 18