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首页> 外文期刊>Gene expression >Antisense targeting of thymidylate synthase (TS) mRNA increases TS gene transcription and TS protein: effects on human tumor cell sensitivity to TS enzyme-inhibiting drugs.
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Antisense targeting of thymidylate synthase (TS) mRNA increases TS gene transcription and TS protein: effects on human tumor cell sensitivity to TS enzyme-inhibiting drugs.

机译：胸苷酸合酶（TS）mRNA的反义靶向增加了TS基因的转录和TS蛋白：对人类肿瘤细胞对TS酶抑制药物敏感性的影响。

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摘要

Thymidylate synthase (TS) catalyses the only de novo pathway to produce thymidylate for DNA replication and repair and is an important target for cancer chemotherapy. Preexisting or acquired drug resistance in tumor cells limits clinical efficacy of TS-targeting drugs. Cells selected for higher TS protein activity have decreased sensitivity to TS-targeting chemotherapeutic agents (5-FUdR and raltitrexed). New therapeutic strategies are required to overcome treatment resistance. Among these, upregulation of drug resistance mediators in normal, nontarget cells and/or antisense downregulation of those mediators (alone or in combination with protein-targeting drugs) are candidate strategies. We have targeted human TS mRNA with antisense oligodeoxynucleotides (AS ODNs), complementary to the translation start site (TSS), the coding region, and the 3' untranslated region. We report here that, in response to treatment with a novel TSS-targeting AS ODN 791, TS gene transcription in a human cervical carcinoma cell line (HeLa) was unexpectedly increased by 70%. Interestingly, the increased TS gene transcription and nuclear TS RNA did not elevate levels of total cellular TS mRNA, but did increase TS protein activity by 35% and TS protein level by 150%. Increased TS protein activity and level did not alter proliferation rate or sensitivity to TS-targeting drugs (5-FUdR or raltitrexed). To assess concentration-dependent effects of TS on sensitivity to TS-targeting drugs, incremental increases of TS protein levels were generated by transfection of a mammalian TS expression vector. Increases in TS protein of less than approximately 400% did not significantly affect sensitivity to TS-targeting drugs, while greater TS protein levels did. These data indicate that AS ODNs targeting TS mRNA can upregulate TS expression and activity in a manner dependent on the sequence being targeted, and that there exists a threshold increase (greater than approximately 400-700% in HeLa cells), required to initiate resistance to TS-targeting drugs.
机译：胸苷酸合酶（TS）催化产生DNA的复制和修复胸苷的唯一从头途径，并且是癌症化疗的重要靶标。肿瘤细胞中先前存在或获得的耐药性限制了靶向TS的药物的临床疗效。为提高TS蛋白活性而选择的细胞对TS靶向化疗剂（5-FUdR和raltitrexed）的敏感性降低。需要新的治疗策略来克服治疗耐药性。其中，正常，非靶细胞中耐药介体的上调和/或这些介体（单独或与蛋白靶向药物组合）的反义下调是候选策略。我们已经用反义寡聚脱氧核苷酸（AS ODN）靶向人类TS mRNA，与翻译起始位点（TSS），编码区和3'非翻译区互补。我们在这里报告，响应以新型TSS靶向AS ODN 791的治疗，人类宫颈癌细胞系（HeLa）中的TS基因转录意外地增加了70％。有趣的是，增加的TS基因转录和核TS RNA并未提高总细胞TS mRNA的水平，但确实使TS蛋白活性提高了35％，TS蛋白水平提高了150％。 TS蛋白活性和水平的提高不会改变对TS靶向药物（5-FUdR或raltitrexed）的增殖率或敏感性。为了评估TS对TS靶向药物敏感性的浓度依赖性作用，通过转染哺乳动物TS表达载体产生TS蛋白水平的增量增加。 TS蛋白的增加少于约400％不会显着影响对TS靶向药物的敏感性，而更高的TS蛋白水平却不会。这些数据表明，靶向TS mRNA的AS ODNs可以以依赖于靶向序列的方式上调TS表达和活性，并且存在阈值增加（在HeLa细胞中大于约400-700％），以启动对TS的抗性TS靶向药物。

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