β-Catenin-regulated ALDH1A1 is a Target in Ovarian Cancer Spheroids

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2014 Jun 24

PMID 24954508

Citations 120

Authors

S Condello

C A Morgan

S Nagdas

L Cao

J Turek

T D Hurley

D Matei

Affiliations

Soon will be listed here.

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.

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References

Jian H, Shen X, Liu I, Semenov M, He X, Wang X . Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev. 2006; 20(6):666-74. PMC: 1413283. DOI: 10.1101/gad.1388806. View

Condello S, Cao L, Matei D . Tissue transglutaminase regulates β-catenin signaling through a c-Src-dependent mechanism. FASEB J. 2013; 27(8):3100-12. PMC: 4050431. DOI: 10.1096/fj.12-222620. View

Lawrenson K, Notaridou M, Lee N, Benjamin E, Jacobs I, Jones C . In vitro three-dimensional modeling of fallopian tube secretory epithelial cells. BMC Cell Biol. 2013; 14:43. PMC: 3849984. DOI: 10.1186/1471-2121-14-43. View

Chau W, Ip C, Mak A, Lai H, Wong A . c-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/β-catenin-ATP-binding cassette G2 signaling. Oncogene. 2012; 32(22):2767-81. DOI: 10.1038/onc.2012.290. View

Howes A, Chiang G, Lang E, Ho C, Powis G, Vuori K . The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol Cancer Ther. 2007; 6(9):2505-14. DOI: 10.1158/1535-7163.MCT-06-0698. View

Jackson B, Brocker C, Thompson D, Black W, Vasiliou K, Nebert D . Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Hum Genomics. 2011; 5(4):283-303. PMC: 3392178. DOI: 10.1186/1479-7364-5-4-283. View

Fang D, Nguyen T, Leishear K, Finko R, Kulp A, Hotz S . A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res. 2005; 65(20):9328-37. DOI: 10.1158/0008-5472.CAN-05-1343. View

Chang T, Hughes-Fulford M . Monolayer and spheroid culture of human liver hepatocellular carcinoma cell line cells demonstrate distinct global gene expression patterns and functional phenotypes. Tissue Eng Part A. 2008; 15(3):559-67. PMC: 6468949. DOI: 10.1089/ten.tea.2007.0434. View

Hazlehurst L, Landowski T, Dalton W . Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death. Oncogene. 2003; 22(47):7396-402. DOI: 10.1038/sj.onc.1206943. View

10.

Lengyel E, Burdette J, Kenny H, Matei D, Pilrose J, Haluska P . Epithelial ovarian cancer experimental models. Oncogene. 2013; 33(28):3619-33. PMC: 3990646. DOI: 10.1038/onc.2013.321. View

11.

Wang Y, Krivtsov A, Sinha A, North T, Goessling W, Feng Z . The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010; 327(5973):1650-3. PMC: 3084586. DOI: 10.1126/science.1186624. View

12.

Reuben J, Lee B, Gao H, Cohen E, Mego M, Giordano A . Primary breast cancer patients with high risk clinicopathologic features have high percentages of bone marrow epithelial cells with ALDH activity and CD44⁺CD24lo cancer stem cell phenotype. Eur J Cancer. 2011; 47(10):1527-36. PMC: 3116032. DOI: 10.1016/j.ejca.2011.01.011. View

13.

Steeg P . Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. 2006; 12(8):895-904. DOI: 10.1038/nm1469. View

14.

Morin P . beta-catenin signaling and cancer. Bioessays. 1999; 21(12):1021-30. DOI: 10.1002/(SICI)1521-1878(199912)22:1<1021::AID-BIES6>3.0.CO;2-P. View

15.

Weiswald L, Guinebretiere J, Richon S, Bellet D, Saubamea B, Dangles-Marie V . In situ protein expression in tumour spheres: development of an immunostaining protocol for confocal microscopy. BMC Cancer. 2010; 10:106. PMC: 2851689. DOI: 10.1186/1471-2407-10-106. View

16.

David L, Dulong V, Le Cerf D, Cazin L, Lamacz M, Vannier J . Hyaluronan hydrogel: an appropriate three-dimensional model for evaluation of anticancer drug sensitivity. Acta Biomater. 2007; 4(2):256-63. DOI: 10.1016/j.actbio.2007.08.012. View

17.

Liu H, Radisky D, Wang F, Bissell M . Polarity and proliferation are controlled by distinct signaling pathways downstream of PI3-kinase in breast epithelial tumor cells. J Cell Biol. 2004; 164(4):603-12. PMC: 2171976. DOI: 10.1083/jcb.200306090. View

18.

Frankel A, Buckman R, Kerbel R . Abrogation of taxol-induced G2-M arrest and apoptosis in human ovarian cancer cells grown as multicellular tumor spheroids. Cancer Res. 1997; 57(12):2388-93. View

19.

LEsperance S, Bachvarova M, Tetu B, Mes-Masson A, Bachvarov D . Global gene expression analysis of early response to chemotherapy treatment in ovarian cancer spheroids. BMC Genomics. 2008; 9:99. PMC: 2279123. DOI: 10.1186/1471-2164-9-99. View

20.

Camper S . Beta-catenin stimulates pituitary stem cells to form aggressive tumors. Proc Natl Acad Sci U S A. 2011; 108(28):11303-4. PMC: 3136328. DOI: 10.1073/pnas.1108275108. View