國家衛生研究院 NHRI:Item 3990099045/7022
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    题名: Blockage of Nrf2/AKR1C axis enhanced therapeutic efficacy of oxaliplatin in oxaliplatin resistant gastric cancer cells
    作者: Kuo, C;Chu, C;Huang, C;Chang, J;Pan, W;Chen, L
    贡献者: National Institute of Cancer Research
    摘要: Background: Oxaliplatin is one of the major cytotoxic chemotherapeutic agents for the treatment of advanced gastrointestinal tract cancer, including pancreatic cancer, but the underlying mechanisms of acquired oxaliplatin resistance remain obscured. We previously established an oxaliplatin resistant subline, named TSGH-S3 (S3), from human gastric adenocarcinoma TSGH cells by stepwise exposure to increasing concentration of oxaliplatin. We found that enhanced copper efflux transporter ATP7A and global DNA repair capacity, at least in part, contributed to the development of such phenotype in S3 cells (British Journal of Cancer 97:334–344, 2007). In the present study, we applied global analysis using gene array technology to further investigate the difference between S3 and TSGH cells. Materials and Methods: S3, an oxaliplatin resistant subline, was made resistant to oxaliplatin by continuous selection against increasing drug concentrations from the human gastric adenocarcinoma TSGH cells. Growth inhibitory assay, Western blot analysis, quantitative RT-PCR (qRTPCR), flow cytometry analysis, and RNA interference technology were used to reveal molecular events in this study. Results: According to the result from microarray analysis, the transcripts of aldo-keto reductase 1C subfamily members, including AKR1C1 and AKR1C3, were noted to be highly enriched in S3 cells as compared to TSGH. The enhanced expression of these molecules in S3 cells were further confirmed by qRT-PCR and western blotting. Therefore, we aimed to elucidate the role of AKR1Cs in the development of oxaliplatin resistance. Notably, manipulation of AKR1C activity with specific AKR1C inhibitors or AKR1C-targeted siRNA significantly reversed the oxaliplatin resistance in S3 cells. Since AKR1Cs are classical ARE genes and can be trans-activated by redox-sensitive transcription factor Nrf2, we therefore examined the role of Nrf2 in S3 cells. As the result, knockdown of Nrf2 expression not only decreased the expression level of AKR1C1, AKR1C2, AKR1C3, and other ARE genes, but also significantly reversed oxaliplatin resistance in S3 cells. Conclusions: Taken together, we proposed that activation of Nrf2/AKR1C axis serves as an important regulator of oxaliplatin resistance in this human gastric carcinomas cell model. Thus, manipulation of Nrf2/AKR1C activity may have potential in management of oxaliplatin-refractory gastrointestinal cancers.
    日期: 2012-11
    關聯: European Journal of Cancer. 2012 Nov;48(Suppl. 6):48.
    Link to: http://dx.doi.org/10.1016/S0959-8049(12)71955-X
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0959-8049&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000312763000153
    显示于类别:[陳立宗] 會議論文/會議摘要
    [張俊彥] 會議論文/會議摘要
    [郭靜娟] 會議論文/會議摘要

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