• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The international journal of biochemistry and cell biology >Differential cathepsin responses to inhibitor-induced feedback: E-64 and cystatin C elevate active cathepsin S and suppress active cathepsin L in breast cancer cells
【24h】

Differential cathepsin responses to inhibitor-induced feedback: E-64 and cystatin C elevate active cathepsin S and suppress active cathepsin L in breast cancer cells

机译：差异的表情素对抑制剂诱导的反馈的反应：E-64和胱抑素C升高活性组织蛋白酶s并在乳腺癌细胞中抑制活性组织蛋白酶L.

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Cathepsins are powerful proteases, once referred to as the lysosomal cysteine proteases, that have been implicated in breast cancer invasion and metastasis, but pharmaceutical inhibitors have suffered failures in clinical trials due to adverse side effects. Scientific advancement from lysosomotropic to cell impermeable cathepsin inhibitors have improved efficacy in treating disease, but off-target effects have still been problematic, motivating a need to better understand cellular feedback and responses to treatment with cathepsin inhibitors. To address this need, we investigated effects of E-64 and cystatin C, two broad spectrum cathepsin inhibitors, on cathepsin levels intra- and extracellularly in MDA-MB-231 breast cancer cells. Cathepsins S and L had opposing responses to both E-64 and cystatin C inhibitor treatments with paradoxically elevated amounts of active cathepsin S, but decreased amounts of active cathepsin L, as determined by multiplex cathepsin zymography. This indicated cellular feedback to selectively sustain the amounts of active cathepsin S even in the presence of inhibitors with subnanomolar inhibitory constant values. These differences were identified in cellular locations of cathepsins L and S, trafficking for secretion, co-localization with endocytosed inhibitors, and longer protein turnover time for cathepsin S compared to cathepsin L Together, this work demonstrates that previously underappreciated cellular compensation and compartmentalization mechanisms may sustain elevated amounts of some active cathepsins while diminishing others after inhibitor treatment. This can confound predictions based solely on inhibitor kinetics, and must be better understood to effectively deploy therapies and dosing strategies that target cathepsins to prevent cancer progression. (C) 2016 Elsevier Ltd. All rights reserved.
机译：组织蛋白酶是强大的蛋白酶，一旦称为溶酶体半胱氨酸蛋白酶，就会涉及乳腺癌侵袭和转移，但由于不良副作用，药物抑制剂患有临床试验中的失败。来自溶寡核苷酸不透水的组织蛋白酶抑制剂的科学进步在治疗疾病中具有改善的疗效，但偏离目标效应仍然存在问题，促使需要更好地了解细胞反馈和对组织蛋白酶抑制剂治疗的反应。为了满足这种需求，我们研究了E-64和胱抑素C，两种广谱凋亡抑制剂，在MDA-MB-231乳腺癌细胞中的组织蛋白酶水平和细胞内抑制剂上的影响。 Compepsins S和L对E-64和胱抑素C抑制剂治疗的反应与矛盾的升高量的活性组织蛋白酶S，但是通过多重组织蛋白酶酶谱法测定的活性组织蛋白酶L的量减少。即使在具有亚甲醛抑制恒定值的抑制剂存在下，该表明细胞反馈即使在抑制剂存在下也能选择性地维持活性组织蛋白酶的量。这些差异在组织蛋白酶L和S的细胞位置中，贩运分泌物，与内吞抑血管的共同定位，以及与组织蛋白酶一起相比的蛋白质周转时间较长，这项工作表明，先前被占据了近似的蜂窝补偿和分区化机制在抑制剂治疗后减少其他活性组织蛋白酶的升高量。这可以完全基于抑制剂动力学的预测，并且必须更好地理解，以有效地部署靶向组织蛋白酶以防止癌症进展的疗法和给药策略。 （c）2016 Elsevier Ltd.保留所有权利。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号