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, T. D.
AU - Matei, D.
N1 - Funding Information:
Drs Turek, Matei and Hurley’s work has been funded by the NIH. Dr Matei received funding from the US Department of Veterans Affairs and the American Cancer Society. Dr Hurley holds significant financial equity in SAJE Pharma, LLC. However, none of the work described in this study is related to, based on, or supported by the company
Funding Information:
We thank Dr Jeanette McClintick from the Indiana University Center for Medical Genomics, Dr Malgorzata Kamocha from IBCM and Dr Chirayu Goswami from the Bioinformatics Core for technical assistance. This work was made possible by funding from the US Department of Veterans Affairs to DM and from NIH to TDH (R01-AA018123), DM and JT (R01EB016582).
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 -
