Human colorectal cancer cell lines treated with several inhibitors of PI3Kinase – AKT signaling pathway

Signal transduction processes mediated by phosphatidyl inositol phosphates affect a broad range of cellular processes such as cell cycle progression, migration and cell survival. The protein kinase AKT is one of the major effectors in this signaling network. Chronic AKT activation contributes to oncogenic transformation and tumor development. Therefore, new small drugs were designed to block AKT activity for cancer treatment. Here we characterize the biological effects of the phosphatidyl inositol phosphate analogs SH-5 and SH-6 in colorectal cancer cell lines. We demonstrate that the two compounds did not reduce AKT phosphorylation significantly in the presence of growth factors, but induce a broad range of morphological and transcriptional alterations. Transcriptomic profiling in inhibitor-treated SW480 cells revealed a cluster of down- regulated genes associated with mitosis. Moreover, the treatment of SW480 cells with either SH-5 or SH-6 caused the formation of binucleated cells as a result of a specific abscission defect. The cells were treated with certain inhibitors for 48 hours. We used one sample per cell line treated with DMSO as a control, and one sample for each of the treatments.

磷脂酰肌醇磷酸（phosphatidyl inositol phosphates）介导的信号转导过程，广泛调控细胞周期进程、细胞迁移及细胞存活等多种细胞生命活动。蛋白激酶AKT是该信号通路网络中的核心效应分子之一。持续性AKT激活可驱动致癌转化与肿瘤发生发展。为此，科研人员开发了多款靶向抑制AKT活性的小分子抗癌药物。本研究旨在表征磷脂酰肌醇磷酸类似物SH-5与SH-6在结直肠癌细胞系中的生物学效应。实验结果表明，在生长因子存在的条件下，这两种化合物并未显著降低AKT的磷酸化水平，却可诱导广泛的形态学与转录组学改变。对经抑制剂处理的SW480细胞开展转录组分析（transcriptomic profiling），结果揭示了一组与有丝分裂相关的下调基因簇。此外，用SH-5或SH-6处理SW480细胞后，会因特异性胞质脱落（abscission）缺陷导致双核细胞的形成。所有受试细胞均经对应抑制剂处理48小时。本研究以经二甲基亚砜（DMSO）处理的细胞系样本作为对照，每种药物处理组均设置一份样本。