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

S. Condello, C. A. Morgan, S. Nagdas, L. Cao, J. Turek, Thomas Hurley, Daniela Matei

Research output: Contribution to journalArticle

63 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2297-2308
Number of pages12
JournalOncogene
Volume34
Issue number18
DOIs
StatePublished - Apr 30 2015

Fingerprint

Catenins
Ovarian Neoplasms
Anoikis
Neoplasms
Neoplastic Stem Cells
Gene Regulatory Networks
Peritoneal Cavity
Transcriptome
Heterografts
Small Interfering RNA
Cell Survival
Acetates
Stem Cells
Maintenance
Neoplasm Metastasis
Growth

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids. / Condello, S.; Morgan, C. A.; Nagdas, S.; Cao, L.; Turek, J.; Hurley, Thomas; Matei, Daniela.

In: Oncogene, Vol. 34, No. 18, 30.04.2015, p. 2297-2308.

Research output: Contribution to journalArticle

Condello, S, Morgan, CA, Nagdas, S, Cao, L, Turek, J, Hurley, T & Matei, D 2015, 'β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids', Oncogene, vol. 34, no. 18, pp. 2297-2308. https://doi.org/10.1038/onc.2014.178
Condello S, Morgan CA, Nagdas S, Cao L, Turek J, Hurley T et al. β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids. Oncogene. 2015 Apr 30;34(18):2297-2308. https://doi.org/10.1038/onc.2014.178
Condello, S. ; Morgan, C. A. ; Nagdas, S. ; Cao, L. ; Turek, J. ; Hurley, Thomas ; Matei, Daniela. / β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids. In: Oncogene. 2015 ; Vol. 34, No. 18. pp. 2297-2308.
@article{04b7c3613eae49789920d8a20533e106,
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.",
author = "S. Condello and Morgan, {C. A.} and S. Nagdas and L. Cao and J. Turek and Thomas Hurley and Daniela Matei",
year = "2015",
month = "4",
day = "30",
doi = "10.1038/onc.2014.178",
language = "English",
volume = "34",
pages = "2297--2308",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "18",

}

TY - JOUR

T1 - β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids

AU - Condello, S.

AU - Morgan, C. A.

AU - Nagdas, S.

AU - Cao, L.

AU - Turek, J.

AU - Hurley, Thomas

AU - Matei, Daniela

PY - 2015/4/30

Y1 - 2015/4/30

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84939152538&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84939152538&partnerID=8YFLogxK

U2 - 10.1038/onc.2014.178

DO - 10.1038/onc.2014.178

M3 - Article

C2 - 24954508

AN - SCOPUS:84939152538

VL - 34

SP - 2297

EP - 2308

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 18

ER -