Induction of Thioredoxin-Interacting Protein by a Histone Deacetylase Inhibitor, Entinostat, Is Associated with DNA Damage and Apoptosis in Esophageal Adenocarcinoma.
Induction of Thioredoxin-Interacting Protein by a Histone Deacetylase Inhibitor, Entinostat, Is Associated with DNA Damage and Apoptosis in Esophageal Adenocarcinoma.
复制标题
DOI：
10.1158/1535-7163.mct-17-1240
复制
发表时间：
2018-09
影响因子：
5.7
通讯作者：
Ripley RT
中科院分区：
文献类型：
--
作者：
Feingold PL;Surman DR;Brown K;Xu Y;McDuffie LA;Shukla V;Reardon ES;Crooks DR;Trepel JB;Lee S;Lee MJ;Gao S;Xi S;McLoughlin KC;Diggs LP;Beer DG;Nancarrow DJ;Neckers LM;Davis JL;Hoang CD;Hernandez JM;Schrump DS;Ripley RT
2017 年，估计有 17,000 人被诊断患有食管腺癌 (EAC)，只有不到 20% 的人能存活 5 年。 PET 亲和力表明葡萄糖利用率高，并且在 EAC 中几乎普遍存在。 TXNIP 阻断葡萄糖摄取并表现出促凋亡功能。 EAC 中的较高表达与改善疾病特异性生存、缺乏淋巴结受累、减少神经周围侵袭和增加肿瘤分化有关。我们假设 TXNIP 可能充当肿瘤抑制剂，使 EAC 细胞对标准化疗药物敏感。使用 EAC 细胞系和 Barrett 上皮细胞系。 qRT-PCR、免疫印迹和免疫荧光技术评估基因表达。使用慢病毒RNA转导技术稳定地过表达或敲低TXNIP。小鼠异种移植方法检查了 TXNIP 过度表达后的生长情况。通过膜联蛋白 V 和 ɣH2AX 检测来测量细胞凋亡和 DNA 损伤。使用绿色荧光蛋白-Caspase 3 报告基因测定对内在细胞凋亡的激活进行定量。在培养细胞和食管组织阵列中，与 EAC 相比，Barrett 上皮和正常组织中的 TXNIP 表达较高。 TXNIP 的组成型过度表达降低了增殖、克隆形成和肿瘤异种移植物的生长。顺铂治疗后，TXNIP 过度表达增加，而敲低则消除 DNA 损伤和细胞凋亡。 HDAC 抑制剂恩替司他（目前正在进行临床试验）可上调 TXNIP，并协同增加顺铂介导的 DNA 损伤和细胞凋亡。 TXNIP 是一种肿瘤抑制因子，在 EACC 中下调。它的重新表达使这些细胞对顺铂显着敏感。我们的研究结果支持“启动”策略的 I/II 期评估，以增强 EAC 中传统化疗药物的疗效。
In 2017, an estimated 17,000 individuals were diagnosed with esophageal adenocarcinoma (EAC) and less than 20% will survive 5 years. PET-avidity is indicative of high glucose utilization and is nearly universal in EAC. TXNIP blocks glucose uptake and exhibits pro-apoptotic functions. Higher expression in EAC has been associated with improved disease-specific survival, lack of lymph node involvement, reduced perineural invasion, and increased tumor differentiation. We hypothesized that TXNIP may act as a tumor suppressor that sensitizes EAC cells to standard chemotherapeutics. EAC cell lines and a Barrett’s epithelial cell line were used. qRT-PCR, immunoblot, and immunofluorescence techniques evaluated gene expression. TXNIP was stably over-expressed or knocked down using lentiviral RNA transduction techniques. Murine xenograft methods examined growth following over-expression of TXNIP. Apoptosis and DNA damage were measured by Annexin V and ɣH2AX assays. Activation of the intrinsic apoptosis was quantitated with green fluorescence protein-caspase 3 reporter assay. In cultured cells and an esophageal tissue array, TXNIP expression was higher in Barrett’s epithelia and normal tissue compared to EAC. Constitutive over-expression of TXNIP decreased proliferation, clonogenicity, and tumor xenograft growth. TXNIP overexpression increased whereas knockdown abrogated DNA damage and apoptosis following cisplatin treatment. An HDAC-inhibitor, entinostat (currently in clinical trials), upregulated TXNIP and synergistically increased cisplatin-mediated DNA damage and apoptosis. TXNIP is a tumor suppressor that is down-regulated in EACC. Its re-expression dramatically sensitizes these cells to cisplatin. Our findings support phase I/II evaluation of ‘priming’ strategies to enhance the efficacy of conventional chemotherapeutics in EAC.