國家衛生研究院 NHRI:Item 3990099045/9774
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    題名: Activation of NRF2/ABCC1 axis confers resistance to topoisomerase II poisons in human oral malignancies
    作者: Chen, HH;Huang, YW;Cheng, TT;Lai, WY;Chang, JY;Kuo, CC
    貢獻者: National Institute of Cancer Research
    摘要: Etoposide (VP-16), a DNA topoisomerase II poison, is an important clinical used chemotherapeutic agent for human oral malignancies. An etoposide-resistant cell line, KB-7D, has been generated from human oral epidermoid carcinoma KB cells to investigate the mechanism of action of drug resistance in oral malignancies. Previous studies revealed that KB-7D cells were approximately 50-fold more resistant to etoposide as compared to parental KB cells. It also exhibited cross-resistant to chemotherapeutic agents such as doxorubicin. This multi-drug resistance may be caused by the over-expression of ABCC1, leading to the decrease in drug accumulation in KB-7D cells. Our current work continues the effort to investigate the mechanism of regulation of ABCC1 expression in the etoposide-derived drug resistant cells and subsequently find the molecular target that can be used to restore therapeutic efficacy in chemo-refratory cancers. Down-regulation of ABCC1 by RNA interference and a selective inhibitor, MK-571, significantly enhanced the chemosensitivity to etoposide and doxorubicin in KB and KB-7D cells. To further determine the possible transcriptional factors that regulate the ABCC1 transactivation, the promoter region of ABCC1 was examined. A NRF2 binding sequence, antioxidant responsive element (ARE), has been found locate in the ABCC1 promoter at -470 to -458 upstream from the transcription start site. Real-time RT-PCR and Western blot analyses showed that expression of NRF2 mRNA and protein in KB-7D cells was 1.4 to 1.8 folds higher than those expressed in the parental cells. In addition, Chromatin Immunoprecipitation (ChIP) analysis revealed that NRF2 directly targeted to the ARE sequence in the ABCC1 promoter region. Interestingly, down-regulation of NRF2 decreased the expression of ABCC1 and also increased the chemosensitivity of KB-7D cells against selected anti-cancer drugs. In addition, cells incubated with an NRF2 activator, tBHQ, induced nucleus accumulation of NRF2 and over-expression of ABCC1, resulting in the enhancement of drug-resistance against etoposide or doxorubcin in KB and KB-7D cells. In summary, constitutive activation of NRF2-dependent ABCC1 contributed to the causation of chemoresistance in etoposide-derived drug resistant cells. Blockage of ABCC1 expression by manipulation of the NRF2 signaling pathway enhanced the chemotherapeutic efficacy in cells. Therefore, targeting NRF2 may be able to reverse chemoresistance in chemo-refractory oral malignancies. In addition, development of NRF2 inhibitors may be a new strategy to overcome chemoresistance in human cancers.
    日期: 2011-04
    關聯: Cancer Research. 2011 Apr;71:Abstract number 1528.
    Link to: http://dx.doi.org/10.1158/1538-7445.am2011-1528
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0008-5472&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000209701302156
    顯示於類別:[郭靜娟] 會議論文/會議摘要
    [張俊彥] 會議論文/會議摘要

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