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The effects of proteasome inhibition on angiogenesis and autophagy in human prostate cancer cells.

机译：蛋白酶体抑制对人前列腺癌细胞中血管生成和自噬的影响。

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摘要

The proteasome degrades approximately 80% of intracellular proteins to maintain homeostasis. Proteasome inhibition is a validated therapeutic strategy, and currently, proteasome inhibitor bortezomib is FDA approved for the treatment of MM and MCL. Specific pathways affected by proteasome inhibition have been identified, but mechanisms of the anti-tumor effects of proteasome inhibition are not fully characterized and cancer cells display marked heterogeneity in terms of their sensitivity to proteasome inhibitor induced cell death.; The antitumor effects of proteasome inhibition involve suppression of tumor angiogenesis and vascular endothelial growth factor (VEGF) expression, but the mechanisms involved have not been clarified. In this dissertation I investigated the mechanisms underlying the effects of two proteasome inhibitors, bortezomib and NPI-0052, on VEGF expression in human prostate cancer cells. I found that proteasome inhibitors selectively downregulated hypoxia inducible factor 1alpha (HIF-1alpha) protein and its transcriptional activity to inhibit VEGF expression. Mechanistic studies demonstrated that proteasome inhibitors mediate the induction of the unfolded protein response (UPR) and that downregulation of HIF-1alpha is caused by eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation and translation repression. Importantly, I showed that proteasome inhibitors activated the UPR in some cells but not in others. My observation may have implications for the design of combination regimens that are based on exploiting proteasome inhibitor-induced ER stress.; Although proteasome inhibitors have shown modest activity on prostate cancer, there is general consensus that no single agent is likely to have significant activity in prostate cancer. In the second part of this dissertation I attempted to exploit the effects of proteasome inhibition on the UPR to design a combination therapy that would enhance cancer cell death. Autophagy is a lysosome dependent degradation pathway that functions to eliminate long-lived protein and subcellular structures. Targeting autophagy has been shown to inhibit tumors in preclinical studies. I found that inhibition of autophagy with chloroquine or 3-methyladenine enhanced proteasome inhibitor induced cell death and the effects were associated with increased intracellular stress as marked by aggresome formation. Multiple cancers appear to be resistant to proteasome inhibition treatment alone. The implications of synergy for the combined inhibition of autophagy and the proteasome would likely apply to other cancers aside from prostate cancer.
机译：蛋白酶体降解大约80％的细胞内蛋白质以维持体内平衡。蛋白酶体抑制是一种经过验证的治疗策略，目前，蛋白酶体抑制剂硼替佐米已获得FDA批准用于MM和MCL的治疗。已经确定了受蛋白酶体抑制作用影响的特定途径，但是蛋白酶体抑制作用的抗肿瘤作用机理尚未得到充分表征，癌细胞对蛋白酶体抑制剂诱导的细胞死亡的敏感性方面表现出明显的异质性。蛋白酶体抑制作用的抗肿瘤作用包括抑制肿瘤血管生成和血管内皮生长因子（VEGF）的表达，但尚未阐明其涉及的机制。在本文中，我研究了两种蛋白酶体抑制剂硼替佐米和NPI-0052对人前列腺癌细胞中VEGF表达的影响的机制。我发现蛋白酶体抑制剂选择性下调缺氧诱导因子1α（HIF-1alpha）蛋白及其转录活性以抑制VEGF表达。机理研究表明，蛋白酶体抑制剂介导了未折叠的蛋白应答（UPR）的诱导，HIF-1alpha的下调是由真核翻译起始因子2alpha（eIF2alpha）磷酸化和翻译抑制引起的。重要的是，我证明了蛋白酶体抑制剂在某些细胞中激活了UPR，但在另一些细胞中却未激活。我的观察结果可能对基于利用蛋白酶体抑制剂诱导的内质网应激的联合治疗方案的设计有影响。尽管蛋白酶体抑制剂已显示出对前列腺癌的适度活性，但普遍共识是没有单一药物可能在前列腺癌中具有显着活性。在本论文的第二部分中，我尝试利用蛋白酶体抑制作用对UPR进行设计，以设计一种可增强癌细胞死亡的联合疗法。自噬是一种依赖溶酶体的降解途径，其作用是消除长寿的蛋白质和亚细胞结构。在临床前研究中已证明靶向自噬可抑制肿瘤。我发现用氯喹或3-甲基腺嘌呤抑制自噬增强了蛋白酶体抑制剂诱导的细胞死亡，并且这种作用与细胞内应激的增加有关，以聚集体形成为特征。多种癌症似乎仅对蛋白酶体抑制治疗有抵抗力。协同作用对自噬和蛋白酶体联合抑制的含义可能适用于除前列腺癌以外的其他癌症。

著录项

  • 作者

    Zhu, Keyi.;

  • 作者单位

    The University of Texas Graduate School of Biomedical Sciences at Houston.;

  • 授予单位 The University of Texas Graduate School of Biomedical Sciences at Houston.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 166 p.
  • 总页数 166
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;
  • 关键词

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