Abstract:
:In 2017, an estimated 17,000 individuals were diagnosed with esophageal adenocarcinoma (EAC), and less than 20% will survive 5 years. Positron emission tomography avidity is indicative of high glucose utilization and is nearly universal in EAC. TXNIP blocks glucose uptake and exhibits proapoptotic 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 epithelial cell line were used. qRT-PCR, immunoblot, and immunofluorescence techniques evaluated gene expression. TXNIP was stably overexpressed or knocked down using lentiviral RNA transduction techniques. Murine xenograft methods examined growth following overexpression of TXNIP. Apoptosis and DNA damage were measured by annexin V and γH2AX 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 epithelia and normal tissue compared with EAC. Constitutive overexpression 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 downregulated in EACC. Its reexpression 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. Mol Cancer Ther; 17(9); 2013-23. ©2018 AACR.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
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,Rdoi
10.1158/1535-7163.MCT-17-1240subject
Has Abstractpub_date
2018-09-01 00:00:00pages
2013-2023issue
9eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-17-1240journal_volume
17pub_type
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0168
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journal_title:Molecular cancer therapeutics
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doi:10.1158/1535-7163.MCT-16-0012
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journal_title:Molecular cancer therapeutics
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doi:10.1158/1535-7163.MCT-14-0968-T
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pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2003-11-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-2398
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pub_type: 杂志文章
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更新日期:2012-04-01 00:00:00
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更新日期:2019-11-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-0640
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doi:10.1158/1535-7163.MCT-13-0924
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
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