Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
Pathol Res Pract. 2019 Nov;215(11):152677. doi: 10.1016/j.prp.2019.152677. Epub 2019 Sep 27.
Sanguinarine (SAG), a benzophenanthridine alkaloid extracted from Sanguinaria canadensis, exerts antioxidant, anti-inflammatory and antiproliferative activities in a variety of malignancies. However, the underlying mechanisms by which SAG affects the tumorigenesis of gastric cancer (GC) are unclear. The common targets of SAG and GC were identified by network pharmacology, and the association of thymocyte selection-associated high mobility group box (TOX) with the clinicopathological characteristics and prognosis of patients with GC was analyzed by using datasets from The Cancer Genome Atlas (TCGA). 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assays, colony formation assays, flow cytometry analysis, and a xenograft tumor model were conducted to assess the effects of SAG on the growth of GC cells, and Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis were used to determine the effects of SAG on the TOX/DNA-PKcs/KU70/80 signaling pathway. We identified 9 collective targets of SAG and GC, of which TOX expression levels were dramatically downregulated in GC tissues compared with adjacent normal tissues, and a low expression of TOX served as an independent prognostic factor of poor survival in patients with GC. SAG suppressed cell viability, colony formation and in vivo tumorigenesis and induced cell apoptosis and cell cycle arrest. Furthermore, SAG increased the expression levels of TOX but decreased those of DNA-PKcs and KU70/80 in GC cells. Our findings indicate that SAG inhibits the tumorigenesis of GC cells by regulating TOX/DNA-PKcs/KU70/80 signaling and may provide therapeutic strategies for the treatment of GC.
血根碱（SAG）是从北美黄连中提取的一种苯并菲啶生物碱，在多种恶性肿瘤中具有抗氧化、抗炎和抗增殖作用。然而，SAG 影响胃癌（GC）发生的潜在机制尚不清楚。通过网络药理学鉴定 SAG 和 GC 的共同靶点，并利用癌症基因组图谱（TCGA）中的数据集分析胸腺细胞选择相关高迁移率族框（TOX）与 GC 患者临床病理特征和预后的关系。通过 3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2-H-四唑溴盐（MTT）测定、集落形成测定、流式细胞术分析和异种移植肿瘤模型来评估 SAG 对 GC 细胞生长的影响，并通过定量实时聚合酶链反应（qRT-PCR）和 Western blot 分析来确定 SAG 对 TOX/DNA-PKcs/KU70/80 信号通路的影响。我们鉴定了 SAG 和 GC 的 9 个共同靶点，其中 GC 组织中 TOX 的表达水平明显低于相邻正常组织，TOX 的低表达是 GC 患者不良生存的独立预后因素。SAG 抑制细胞活力、集落形成和体内肿瘤发生，并诱导细胞凋亡和细胞周期停滞。此外，SAG 增加了 GC 细胞中 TOX 的表达水平，降低了 DNA-PKcs 和 KU70/80 的表达水平。我们的研究结果表明，SAG 通过调节 TOX/DNA-PKcs/KU70/80 信号抑制 GC 细胞的肿瘤发生，可能为 GC 的治疗提供策略。
