Cordycepin Inhibits Cancer Cell Proliferation and Angiogenesis through a DEK Interaction via ERK Signaling in Cholangiocarcinoma
Cordycepin Inhibits Cancer Cell Proliferation and Angiogenesis through a DEK Interaction via ERK Signaling in Cholangiocarcinoma
复制标题
虫草素通过 ERK 信号传导与 DEK 相互作用抑制胆管癌中的癌细胞增殖和血管生成
DOI：
10.1124/jpet.119.263202
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发表时间：
2020-05-01
影响因子：
3.5
通讯作者：
Ren, Xiangshan
中科院分区：
文献类型：
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作者：
Liu, Tesi;Zhu, Guang;Ren, Xiangshan
胆管癌（CCA）是一种起源于胆管上皮细胞的恶性肿瘤，其预后差。临床结果仍然令人失望，因此迫切需要更有效的治疗方案。虫草素是一种传统中药，具有多种抗肿瘤药理作用，但其作用机制尚未完全阐明。本文采用MTT法和克隆形成实验，研究了虫草素对CCA细胞的生长抑制作用，并发现虫草素对CCA细胞的生长抑制具有时间和剂量依赖性。流式细胞仪和Hoechst染色显示虫草素通过细胞外信号调节激酶（ERK）1/2的失活诱导肿瘤细胞凋亡。此外，虫草素显着降低CCA在体外的血管生成能力，通过管形成试验。我们还发现虫草素抑制DEK的表达，通过使用Western blot检测。DEK作为一种致癌蛋白，在各种胃肠道肿瘤中过表达。DEK沉默抑制CCA细胞活力和血管生成，但不通过Western印迹和流式细胞术确定的凋亡诱导。此外，虫草素通过下调DEK、磷酸化ERK 1/2 CD 31和血管性血友病因子（vWF）的表达，显著抑制异种移植模型中的肿瘤生长和血管生成能力。综上所述，我们证明虫草素通过下调ERK信号通路抑制CCA细胞增殖和血管生成，并与DEK相互作用。这些数据表明，虫草素可能成为CCA临床治疗和改善预后的新药物。虫草素提供了多种抗肿瘤策略，但其机制尚未完全阐明，特别是对胆管癌（CCA）的作用。我们报道了虫草素抑制CCA细胞的活力，通过细胞外信号调节激酶1/2失活和DEK抑制诱导细胞凋亡，并降低CCA在体内和体外的血管生成能力。
Cholangiocarcinoma (CCA) is a malignant tumor that arises from the epithelial cells of the bile duct and is notorious for its poor prognosis. The clinical outcome remains disappointing, and thus more effective therapeutic options are urgently required. Cordycepin, a traditional Chinese medicine, provides multiple pharmacological strategies in antitumors, but its mechanisms have not been fully elucidated. In this study, we reported that cordycepin inhibited the viability and proliferation capacity of CCA cells in a time- and dose-dependent manner determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and colony formation assay. Flow cytometry and Hoechst dye showed that cordycepin induced cancer cell apoptosis via extracellular signal-regulated kinase (ERK) 1/2 deactivation. Moreover, cordycepin significantly reduced the angiogenetic capabilities of CCA in vitro as examined by tube formation assay. We also discovered that cordycepin inhibited DEK expression by using Western blot assay. DEK serves as an oncogenic protein that is overexpressed in various gastrointestinal tumors. DEK silencing inhibited CCA cell viability and angiogenesis but not apoptosis induction determined by Western blot and flow cytometry. Furthermore, cordycepin significantly inhibited tumor growth and angiogenic capacities in a xenograft model by downregulating the expression of DEK, phosphorylated ERK1/2 CD31 and von Willebrand factor (vWF). Taken together, we demonstrated that cordycepin inhibited CCA cell proliferation and angiogenesis with a DEK interaction via downregulation in ERK signaling. These data indicate that cordycepin may serve as a novel agent for CCA clinical treatment and prognosis improvement. SIGNIFICANCE STATEMENT Cordycepin provides multiple strategies in antitumors, but its mechanisms are not fully elucidated, especially on cholangiocarcinoma (CCA). We reported that cordycepin inhibited the viability of CCA cells, induced apoptosis via extracellular signal-regulated kinase 1/2 deactivation and DEK inhibition, and reduced the angiogenetic capabilities of CCA both in vivo and in vitro.