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首页> 外文学位 >Elucidation of the roles of cyclooxygenase-2 and prostaglandin E2 in human esophageal squamous cell carcinoma.
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Elucidation of the roles of cyclooxygenase-2 and prostaglandin E2 in human esophageal squamous cell carcinoma.

机译：阐明了环氧合酶2和前列腺素E2在人食道鳞状细胞癌中的作用。

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摘要

Overexpression of cyclooxygenase-2 (COX-2) and elevation of its product prostaglandin E2 (PGE2) are implicated in the pathogenesis of human esophageal squamous cell carcinoma. COX-inhibitors also have been demonstrated to overcome multidrug resistance (MDR) in some cancer cells. Therefore, our studies are designed to investigate the role of COX-2 and PGE2 in cell proliferation and drug resistance on human esophageal squamous cell carcinoma cells.PGE2 stimulated cell proliferation of HKESC-1, a human esophageal squamous cell carcinoma cell line. PGE2 exerts its effects through four subtypes of G-protein-coupled receptors, namely EP1 to EP4. In this regard, we showed that all four EP receptor subtypes were expressed in a panel of human esophageal squamous cell carcinoma cell lines (HKESC-1, HKESC-2, HKESC-3, KYSE150, and EC109). Further characterization by pharmacological and RNA interference approaches revealed that EP2 receptor mediated the mitogenic effect of PGE 2 in HKESC-1 cells. EP2 receptor agonist butaprost mimicked the mitogenic effect of PGE2, whereas knockdown of the EP2 receptor attenuated the PGE2-induced proliferation. In relation to the signaling mechanism, PGE2 and butaprost induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whose down-regulation by RNA interference significantly attenuated PGE2-induced cell proliferation. Moreover, ERK1/2 activation by PGE2 was completely abolished by protein kinase C (PKC) inhibitor, Ro-31-8425. In addition, PGE2 and butaprost increased c-Fos expression and activator protein-1 (AP-1) transcriptional activity, which were abolished by the ERK1/2 kinase inhibitor, U0126. AP-1-binding inhibitor, curcumin, also partially reversed the mitogenic effect of PGE2. Apart from c-Fos, PGE2 also increased c-Myc expression and its association with the binding partner Max. Knockdown of c-Myc by RNA interference attenuated PGE 2-induced cell proliferation. Further mechanistic study revealed that PGE2 increased the protein stability and nuclear accumulation of c-Myc via phosphorylation on serine 62 in an ERK1/2-dependent manner. Moreover, the effect of PGE2 on c-Myc expression was mimicked by butaprost. These findings suggest that PGE2 promotes cell proliferation via EP2/PKC/ERK-dependent induction of c-Fos and c-Myc expression in human esophageal squamous cell carcinoma cells.In the event to assess the involvement of COX in cancer cell drug resistance, different COX-inhibitors (indomethacin, SC236, SC560, nimesulide and NS398) were employed. They all substantially suppressed PGE2 production to a similar extent. However, only the non-selective COX inhibitor indomethacin and the COX-2 selective inhibitor SC236 enhanced cytotoxic effects of doxorubicin on HKESC-1 and HKESC-2 cells, and these effects could not be reversed by the addition of PGE2. Knockdown of COX-2 also failed to mimic the enhancing effect of indomethacin or SC236 on cytotoxicity, implicating that their action is COX- and PGE2-independent. To this end, we observed that indomethacin and SC236 directly functioned as non-competitive inhibitors of P-glycoprotein (P-gp), which were manifested as reduction of P-gp ATPase activity. Collectively, these findings suggest that the direct inhibitory effect of indomethacin and SC236 may contribute to their ability to increase the intracellular retention of doxorubicin and thus enhance its cytotoxicity. (Abstract shortened by UMI.)
机译：环氧合酶-2（COX-2）的过表达和其产物前列腺素E2（PGE2）的升高与人类食管鳞状细胞癌的发病机制有关。还证明了COX抑制剂可克服某些癌细胞中的多药耐药性（MDR）。因此，本研究旨在探讨COX-2和PGE2在人食管鳞癌细胞增殖和耐药中的作用.PGE2刺激人食管鳞状细胞癌细胞系HKESC-1的细胞增殖。 PGE2通过G蛋白偶联受体的四个亚型，即EP1至EP4发挥作用。在这方面，我们显示了全部四种EP受体亚型均在一组人类食道鳞状细胞癌细胞系（HKESC-1，HKESC-2，HKESC-3，KYSE150和EC109）中表达。通过药理和RNA干扰方法的进一步表征显示，EP2受体介导HKESC-1细胞中PGE 2的促有丝分裂作用。 EP2受体激动剂Butaprost模仿了PGE2的促有丝分裂作用，而敲低EP2受体则减弱了PGE2诱导的增殖。关于信号传导机制，PGE2和丁巴前列素诱导细胞外信号调节激酶1/2（ERK1 / 2）的磷酸化，其受RNA干扰的下调显着减弱了PGE2诱导的细胞增殖。此外，蛋白激酶C（PKC）抑制剂Ro-31-8425完全消除了PGE2激活的ERK1 / 2。此外，PGE2和butaprost增加了c-Fos表达和激活蛋白1（AP-1）转录活性，这被ERK1 / 2激酶抑制剂U0126取消。 AP-1结合抑制剂姜黄素也可以部分逆转PGE2的促有丝分裂作用。除了c-Fos，PGE2还增加了c-Myc的表达及其与结合伴侣Max的关联。 RNA干扰抑制c-Myc减弱了PGE 2诱导的细胞增殖。进一步的机理研究表明，PGE2通过ERK1 / 2依赖性的丝氨酸62上的磷酸化作用提高了c-Myc的蛋白质稳定性和核积累。此外，butaprost模仿了PGE2对c-Myc表达的作用。这些发现表明PGE2通过EP2 / PKC / ERK依赖性诱导人食管鳞状细胞癌细胞中c-Fos和c-Myc表达来促进细胞增殖。为了评估COX与癌细胞耐药性的关系，使用了COX抑制剂（吲哚美辛，SC236，SC560，尼美舒利和NS398）。它们都以相似的程度基本上抑制了PGE 2的产生。但是，只有非选择性COX抑制剂吲哚美辛和COX-2选择性抑制剂SC236增强了阿霉素对HKESC-1和HKESC-2细胞的细胞毒性作用，并且添加PGE2不能逆转这些作用。降低COX-2的活性也不能模仿吲哚美辛或SC236对细胞毒性的增强作用，暗示它们的作用独立于COX和PGE2。为此，我们观察到吲哚美辛和SC236直接充当P-糖蛋白（P-gp）的非竞争性抑制剂，表现为P-gp ATPase活性降低。总的来说，这些发现表明消炎痛和SC236的直接抑制作用可能有助于它们增加阿霉素的细胞内滞留从而增强其细胞毒性的能力。 （摘要由UMI缩短。）

著录项

  • 作者

    Yu, Le.;

  • 作者单位

    The Chinese University of Hong Kong (Hong Kong).;

  • 授予单位 The Chinese University of Hong Kong (Hong Kong).;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 198 p.
  • 总页数 198
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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