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首页> 外文期刊>Molecular cancer therapeutics >Targeting Ribonucleotide Reductase M2 and NF-kappa B Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer
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Targeting Ribonucleotide Reductase M2 and NF-kappa B Activation with Didox to Circumvent Tamoxifen Resistance in Breast Cancer

机译：靶向核糖核苷酸还原酶M2和NF-Kappa B激活与致催害患者在乳腺癌中避免他莫氧基抗性

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Tamoxifen is widely used as an adjuvant therapy for patients with estrogen receptor (ER alpha)-positive tumors. However, the clinical benefit is often limited because of the emergence of drug resistance. In this study, overexpression of ribonucleotide reductase M2 (RRM2) in MCF-7 breast cancer cells resulted in a reduction in the effectiveness of tamoxifen, through down-regulation of ER alpha 66 and upregulation of the 36-kDa variant of ER (ER alpha 36). We identified that NF-kappa B, HIF1 alpha, and MAPK/JNK are the major pathways that are affected by RRM2 overexpression and result in increased NF-kappa B activity and increased protein levels of EGFR, HER2, IKKs, Bcl-2, RelB, and p50. RRM2-overexpressing cells also exhibited higher migratory and invasive properties. Through time-lapse microscopy and protein profiling studies of tamoxifen-treated MCF-7 and T-47D cells, we have identified that RRM2, along with other key proteins, is altered during the emergence of acquired tamoxifen resistance. Inhibition of RRM2 using siRRM2 or the ribonucleotide reductase (RR) inhibitor didox not only eradicated and effectively prevented the emergence of tamoxifen-resistant populations but also led to the reversal of many of the proteins altered during the process of acquired tamoxifen resistance. Because didox also appears to be a potent inhibitor of NF-kappa B activation, combining didox with tamoxifen treatment cooperatively reverses ER-alpha alterations and inhibits NF-kappa B activation. Finally, inhibition of RRM2 by didox reversed tamoxifen-resistant in vivo tumor growth and decreased in vitro migratory and invasive properties, revealing a beneficial effect of combination therapy that includes RRM2 inhibition to delay or abrogate tamoxifen resistance. (C) 2015 AACR.
机译：Tamoxifen广泛用作雌激素受体（ERα）阳性肿瘤患者的辅助治疗。然而，由于耐药性的出现，临床益处通常是有限的。在该研究中，在MCF-7乳腺癌细胞中的核糖核苷酸还原酶M2（RRM2）的过表达导致他莫昔芬的有效性降低，通过ERα66的下调和er的36-KDA变体的上调（ERα 36）。我们鉴定了NF-Kappa B，HIF1α和MAPK / JNK是受RRM2过表达影响的主要途径，导致NF-Kappa B活性增加和蛋白质水平增加，EGFR，HER2，IKKS，BCL-2，Relb和p50。 RRM2过度抑制细胞也表现出更高的迁移和侵袭性。通过延时显微镜和Tamoxifen处理的MCF-7和T-47D细胞的蛋白质分析研究，我们已经鉴定了RRM2以及其他关键蛋白在获得的他莫莫氧基抗性的出现期间改变。使用SiRRM2或核糖核苷酸还原酶（RR）抑制剂抑制RRM2的抑制不仅是根除和有效地防止他莫氧基抗性群体的出现，而且还导致了在获得的他莫氧基抗性过程中改变的许多蛋白质的逆转。由于DIDOX也似乎是NF-Kappa B激活的有效抑制剂，所以将DOTOX与他莫昔芬治疗组合协同逆转ER-α改变并抑制NF-Kappa B活化。最后，抑制RRM2的毒素逆转他莫氧基抗性的体内肿瘤生长并减少了体外迁移和侵袭性，揭示了组合治疗的有益效果，其包括RRM2抑制延迟或废除他莫莫氧基抗性。 （c）2015年AACR。

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  • 来源
    《Molecular cancer therapeutics》 |2015年第11期|共11页
  • 作者

    Shah Khyati N.; Wilson Elizabeth A.; Malla Ritu; Elford Howard L.; Faridi Jesika S.;

  • 作者单位

    Univ Pacific Thomas J Long Sch Pharm &

    Hlth Sci Dept Physiol &

    Pharmacol Stockton CA 95211 USA;

    Univ Pacific Thomas J Long Sch Pharm &

    Hlth Sci Dept Physiol &

    Pharmacol Stockton CA 95211 USA;

    Univ Pacific Thomas J Long Sch Pharm &

    Hlth Sci Dept Physiol &

    Pharmacol Stockton CA 95211 USA;

    Mol Hlth Inc Richmond VA USA;

    Univ Pacific Thomas J Long Sch Pharm &

    Hlth Sci Dept Physiol &

    Pharmacol Stockton CA 95211 USA;

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  • 正文语种 eng
  • 中图分类 肿瘤学;
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