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Inducing cellular senescence in cancer.

机译：在癌症中诱导细胞衰老。

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摘要

Cellular senescence is a permanent cell cycle arrest that is induced as a response to cellular stress. Replicative senescence is a well-described mechanism that limits the replicative capacity of cells and must be overcome by cancer cells. Oncogene-induced senescence (OIS) is a form of premature senescence and a potent tumor suppressor mechanism. OIS is induced in normal cells as a result of deregulated oncogene or tumor suppressor gene expression. An exciting area of research is the identification of novel targets that induce senescence in cancer cells as a therapeutic approach. In this study, a novel mechanism is described where the inhibition of Hsp90 in small cell lung cancer (SCLC) cells induced premature senescence rather than cell death. The senescence induced following Hsp90 inhibition was p21-dependent and the loss of p21 allowed SCLC cells to bypass the induction of senescence. Additionally, we identified a novel mechanism where the depletion of PKCiota induced senescence in glioblastoma multiforme (GBM) cells. PKCiota depletion-induced senescence did not activate the DNA-damage response pathway and was p21-dependent. Further perturbations of mitosis, using an aurora kinase inhibitor, increased the number of senescent cells when combined with PKCiota depletion. This suggests that PKCiota depletion-induced senescence involves defects in mitotic progression. Senescent glioblastoma cells at a basal level of senescence in culture, induced by p21 overexpression, and induced after PKCiota depletion had aberrant centrosomes. Mitotic slippage is an early exit from mitosis without cell division that occurs when the spindle assembly checkpoint (SAC) is not satisfied. Senescent glioblastoma cells had multiple markers of mitotic slippage. Therefore, PKCiota depletion-induced senescence involves mitotic slippage and results in aberrant centrosomes. A U87MG cell line with a doxycycline-inducible shRNA targeting PKCiota was developed to deplete PKCiota in established xenografts. PKCiota was depleted in established glioblastoma xenografts in mice and resulted in decreased cell proliferation, delayed tumor growth and improved survival. This study has demonstrated that both Hsp90 and PKCiota are novel targets to induce senescence in cancer cells as a potential therapeutic approach.
机译：细胞衰老是由于对细胞应激的反应而诱导的永久性细胞周期停滞。复制衰老是一种众所周知的机制，它限制了细胞的复制能力，必须被癌细胞克服。癌基因诱导的衰老（OIS）是过早衰老的一种形式，是一种有效的肿瘤抑制机制。由于癌基因或肿瘤抑制基因表达失控，在正常细胞中诱导出OIS。激动人心的研究领域是确定诱导癌细胞衰老的新靶点作为治疗方法。在这项研究中，描述了一种新的机制，其中在小细胞肺癌（SCLC）细胞中抑制Hsp90会导致过早衰老而不是细胞死亡。 Hsp90抑制后诱导的衰老是p21依赖性的，p21的丢失使SCLC细胞绕过了衰老的诱导。此外，我们确定了一种新型机制，其中PKCiota的耗竭在胶质母细胞瘤多形性（GBM）细胞中诱导衰老。 PKCiota耗竭诱导的衰老不会激活DNA损伤反应途径，而是p21依赖性的。当与PKCiota耗竭结合时，使用极光激酶抑制剂对有丝分裂的进一步干扰会增加衰老细胞的数量。这表明PKCiota耗竭诱导的衰老涉及有丝分裂进程的缺陷。 p21过表达诱导和PKCiota耗竭后诱导的衰老的胶质母细胞瘤细胞在培养中处于基础衰老水平，其中心体异常。有丝分裂滑移是不满足纺锤体检查点（SAC）时发生的无细胞分裂的有丝分裂的早期退出。衰老的胶质母细胞瘤细胞具有多种有丝分裂滑行的标记。因此，PKCiota耗竭诱导的衰老涉及有丝分裂滑移并导致异常的中心体。开发了具有靶向PKCiota的强力霉素可诱导shRNA的U87MG细胞系，以耗尽已建立的异种移植物中的PKCiota。 PKCiota在小鼠中已建立的胶质母细胞瘤异种移植物中耗竭，导致细胞增殖减少，肿瘤生长延迟和存活率提高。这项研究表明，Hsp90和PKCiota都是诱导癌细胞衰老的新靶标，是一种潜在的治疗方法。

著录项

  • 作者

    Restall, Ian J.;

  • 作者单位

    University of Ottawa (Canada).;

  • 授予单位 University of Ottawa (Canada).;
  • 学科 Biology Cell.;Health Sciences Oncology.;Chemistry Biochemistry.
  • 学位 Ph.D.
  • 年度 2013
  • 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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