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Sensitization of human colorectal cancer cells to paclitaxel- induced apoptosis by inhibition of MEK/ERK pathway is caspase-4 dependent

机译:通过抑制MEK / ERK途径使大肠癌细胞对紫杉醇诱导的细胞凋亡的敏感性取决于caspase-4

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摘要

Our previous studies have shown that paclitaxel induces the endoplasmic reticulum (ER) stress response in colorectal cancer (CRC) cells. Inhibition of MEK/ERK pathway sensitized CRC cells to paclitaxel-induced apoptosis by down-regulation of GRP78. In here, we report that induction of apoptosis by paclitaxel when GRP78 is down-regulated involves activation of caspase caspase-3, caspase-4, and caspase-9. Caspase-4 seemed to be the apical caspase in that caspase-4 activation occurred before activation of caspase-9 and caspase-3. Co-immunoprecipitation studies revealed that GRP78 is physically associated with caspase-4 before and after treatment with paclitaxel. Taken together, these results indicate that GRP78 might be a novel mechanism underlying resistance of CRC cells to microtubule-targeting drugs by binding to and inhibition of caspase-4. Combination of compounds capable of suppressing GRP78 might be a golden approach for improving the effectiveness of taxanes in treatment of CRC.
机译:我们以前的研究表明,紫杉醇在大肠癌(CRC)细胞中诱导内质网(ER)应激反应。 MEK / ERK途径的抑制通过下调GRP78来使CRC细胞对紫杉醇诱导的细胞凋亡产生敏感性。在这里,我们报告说,当GRP78被下调时,紫杉醇诱导的凋亡涉及caspase caspase-3,caspase-4和caspase-9的激活。 caspase-4似乎是顶端的caspase,因为caspase-4激活发生在caspase-9和caspase-3激活之前。免疫共沉淀研究表明,紫杉醇治疗前后,GRP78与caspase-4物理相关。两者合计,这些结果表明,GRP78可能是一种新的机制,其通过与caspase-4结合和抑制而使CRC细胞对靶向微管的药物产生抗性。能够抑制GRP78的化合物的组合可能是提高紫杉烷类药物治疗CRC疗效的黄金方法。

著录项

  • 来源
    《Recent researches in modern medicine》|2011年|p.268-276|共9页
  • 会议地点 Cambridge(GB);Cambridge(GB);Cambridge(GB);Cambridge(GB);Cambridge(GB);Cambridge(GB);Cambridge(GB);Cambridge(GB);Cambridge(GB);Cambridge(GB);Cambridge(GB);Cambridge(GB)
  • 作者单位

    Clinical Pharmacy Department Jordan University of Science Technology Irbid 22110, Jordan;

    Faculty of Science and arts Jordan university of Science Technology Irbid 22110, Jordan. JORDAN;

    Faculty of Science and arts Jordan university of Science Technology Irbid 22110, Jordan. JORDAN;

  • 会议组织
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 基础医学;
  • 关键词

    colon cancer; paclitaxel; UPR; GRP78; apoptosis;

    机译:结肠癌;紫杉醇普遍定期审议; GRP78;凋亡;

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