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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid
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Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

机译：二氢叶酸还原酶敲低的关键作用在2-羟基油酸的抗癌活性

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摘要

α-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyo-leic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of dihydrofolate reductase (DHFR), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of DHFR, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and PARP degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit DHFR but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of DHFR, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.
机译：α-羟基-9-顺式十八烯酸，一种合成的脂肪酸，可改变脂质膜的组成和结构。 2-羟基-乙酸（HOA）由于其有效而无毒的抗癌活性而引起了人们的兴趣。它在人肺癌（A549）细胞中诱导细胞周期停滞，并在人白血病（Jurkat）细胞中诱导凋亡。这两个途径可以解释HOA如何诱导多种癌症的消退。我们显示HOA抑制了负责氢四氢叶酸（THF）合成的酶二氢叶酸还原酶（DHFR）的表达。在没有DHFR参与的情况下容易产生THF的亚叶酸逆转了HOA在A549和Jurkat细胞中的抗肿瘤作用，以及对A549细胞中cyclin D和cdk2以及Jurkat细胞中DNA和PARP降解的抑制作用。这种作用是非常特殊的，因为桉树酸（HOA的类似物）或其他脂质均无法改变A549或Jurkat细胞的生长。 THF是DNA合成必需的辅助因子。因此，DNA合成的损伤似乎是与HOA处理后癌细胞引起的不同反应有关的共同机制，即细胞周期停滞或凋亡。与甲氨蝶呤等其他抗叶酸药物相比，HOA不能直接抑制DHFR，而是抑制其表达，这种作用方式具有一定的治疗优势。这些结果不仅证明了脂肪酸对DHFR表达的影响，而且强调了HOA被用作抗癌的广谱药物的潜力。

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    Victoria Llado; Silvia Teres; Monica Higuera; Rafael Alvarez; Maria Antonia Noguera-Salva; John E. Halver; Pablo V. Escriba; Xavier Busquets;

  • 作者单位

    Laboratory of Cell Biology , Department of Biology, Institut Universitari d'Investigacions en Ciencies de la Salut, University of the Balearic Islands, E-07122 Palma de Mallorca, Spain;

    Laboratory of Molecular Cell Biomedicine, Department of Biology, Institut Universitari d'Investigacions en Ciencies de la Salut, University of the Balearic Islands, E-07122 Palma de Mallorca, Spain;

    Laboratory of Molecular Cell Biomedicine, Department of Biology, Institut Universitari d'Investigacions en Ciencies de la Salut, University of the Balearic Islands, E-07122 Palma de Mallorca, Spain;

    Laboratory of Molecular Cell Biomedicine, Department of Biology, Institut Universitari d'Investigacions en Ciencies de la Salut, University of the Balearic Islands, E-07122 Palma de Mallorca, Spain;

    Laboratory of Molecular Cell Biomedicine, Department of Biology, Institut Universitari d'Investigacions en Ciencies de la Salut, University of the Balearic Islands, E-07122 Palma de Mallorca, Spain;

    School of Aquatic and Fishery Sciences, University of Washington, Seattle, WA 98195;

    Laboratory of Molecular Cell Biomedicine, Department of Biology, Institut Universitari d'Investigacions en Ciencies de la Salut, University of the Balearic Islands, E-07122 Palma de Mallorca, Spain;

    Laboratory of Cell Biology , Department of Biology, Institut Universitari d'Investigacions en Ciencies de la Salut, University of the Balearic Islands, E-07122 Palma de Mallorca, Spain;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    anticancer; DNA; membrane-lipid therapy; neoplasia; nutrigenetics;

    机译：抗癌脱氧核糖核酸;膜脂治疗;肿瘤营养遗传学;

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