β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids.
β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids.
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癌细胞在非贴壁培养条件下形成三维(3D)多细胞聚集体(或球体)。在卵巢癌(OC)中，球体作为癌细胞在腹膜腔内扩散的载体，保护细胞免受环境应激诱导的失巢凋亡。为了确定OC球体中新的靶向分子，我们研究了在三维(3D)培养条件下与传统单层培养条件下上调的基因表达谱和网络。我们发现ALDH1A1是一种肿瘤干细胞标记物，在OC球体中过表达，并直接与β-连环蛋白途径的关键元件有关。在OC球体中，B-连环蛋白功能和ALDH1A1的表达在单层和连续的球体中增加，这表明3D聚集体在具有干细胞特征的细胞中丰富。B-连环蛋白敲除降低了ALDH1A1的表达水平，β-连环蛋白与ALDH1A1启动子共沉淀，提示ALDH1A1是一个直接的β-连环蛋白靶标。小干扰RNA介导的β-catenin基因敲除和A37(这里首次描述的一种新的ALDH1A1小分子酶抑制剂)都破坏了OC球体的形成和细胞活力(p<；0.001)。在OC异种移植模型中，B-连环蛋白基因敲除可抑制肿瘤生长和腹膜转移。这些数据有力地支持了β-连环蛋白调节的ALDH1A1在维持OC球体中的作用，并提出了针对这一细胞群体的新的ALDH1A1抑制剂。
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 three dimensional (3D) versus 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. B-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. B-catenin knockdown decreased ALDH1A1 expression levels and β-catenin coimmunoprecipitated with the ALDH1A1 promoter, suggesting that ALDH1A1 is a direct β-catenin target. Both siRNA mediated β-catenin knockdown and A37, a novel ALDH1A1 small molecule enzymatic inhibitor described here for the first time, disrupted OC spheroid formation and cell viability (p<0.001). B-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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