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首页> 外文学位 >The role of the Akt/TSC/mTOR signaling pathway in Kaposi's sarcoma-associated virus G protein-coupled receptor neoplasia.
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The role of the Akt/TSC/mTOR signaling pathway in Kaposi's sarcoma-associated virus G protein-coupled receptor neoplasia.

机译：Akt / TSC / mTOR信号通路在卡波西氏肉瘤相关病毒G蛋白偶联受体肿瘤中的作用。

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摘要

Kaposi's sarcoma (KS), a multifocal vascular neoplasm, is the most frequent cancer arising in HIV-infected individuals and in immunosuppressed patients. KS is caused by the KS-associated herpesvirus (KSHV). A single lytic gene of KSHV genes, G protein-coupled receptor (vGPCR), is sufficient to induce Kaposi-like sarcomas in mice. This vGPCR has been shown to promote the activation of PI3K/Akt, involved in transformation of endothelial cells. However, the Akt downstream effectors required for vGPCR to promote Kaposi's sarcomagenesis are still unknown.;Here, we have found that vGPCR induces the phosphorylation and inactivation of tuberin (TSC2), promoting the activation of mTOR. Moreover, over-activation of TSC/mTOR is sufficient to render endothelial cells oncogenic. Treatment with rapamycin (mTOR inhibitor) efficiently prevented the growth of vGPCR tumors in vivo. Collectively, these results implicate the mTOR signaling route in Kaposi's sarcomagenesis and provide experimental evidence demonstrating that drugs targeting mTOR may represent an effective mechanism-based therapy for the treatment of KS.;We have observed that, although rapamycin has been shown to be an efficient therapy for patients with iatrogenic or classic KS, the activity of Akt was transiently increased in vGPCR-expressing endothelial cells (EC-vGPCR). We therefore investigated the efficacy of PI-103, a novel dual PI3Kalpha/mTOR inhibitor, in preventing vGPCR transformation. PI-103 treatment effectively and independently blocked the activation of both PI3K and mTOR in EC-vGPCR. This resulted in the effective inhibition of endothelial cell proliferation and survival in vitro, and tumor growth in vivo, suggesting that PI-103 may be an effective therapeutic option for the treatment of KS.;We also found that the angiogenic growth factors secreted by EC-vGPCR can induce the activity of mTOR in endothelial cells, suggesting that vGPCR regulates mTOR through both direct and indirect (paracrine) mechanisms. In addition, we found that the effect of rapamycin on vGPCR sarcomagenesis is not dependent on the direct activation of mTOR in vGPCR-expressing cells. Rather, the profound sensitivity of these tumors to rapamycin treatment may be due, in part, to the inhibition of the paracrine activation of mTOR in neighboring (bystander) cells by the angiogenic factors elaborated by EC-vGPCR. Collectively, these results support the key role of paracrine transforming mechanisms in vGPCR sarcomagenesis.
机译：卡波济肉瘤（KS）是一种多灶性血管肿瘤，是在HIV感染者和免疫抑制患者中最常见的癌症。 KS是由KS相关的疱疹病毒（KSHV）引起的。 KSHV基因的一个单一裂解基因，即G蛋白偶联受体（vGPCR），足以在小鼠中诱导卡波西氏样肉瘤。该vGPCR已经显示出促进PI3K / Akt的活化，其参与内皮细胞的转化。但是，vGPCR促进卡波西氏肉瘤形成所需的Akt下游效应子仍然未知。在这里，我们发现vGPCR诱导了Tuberin（TSC2）的磷酸化和失活，从而促进了mTOR的激活。此外，TSC / mTOR的过度激活足以使内皮细胞致癌。雷帕霉素（mTOR抑制剂）治疗有效地阻止了vGPCR肿瘤在体内的生长。总的来说，这些结果暗示了mTOR信号转导途径在卡波济肉瘤的发生中，并提供了实验证据，证明靶向mTOR的药物可能代表了一种有效的基于机制的治疗KS的疗法。对于医源性或经典KS患者的治疗，表达vGPCR的内皮细胞（EC-vGPCR）中Akt的活性瞬时增加。因此，我们研究了新型的PI3Kalpha / mTOR双重抑制剂PI-103在预防vGPCR转化中的功效。 PI-103治疗有效且独立地阻断了EC-vGPCR中PI3K和mTOR的激活。这导致有效抑制内皮细胞的体外增殖和存活以及体内肿瘤的生长，这表明PI-103可能是治疗KS的有效治疗选择。；我们还发现EC分泌的血管生成因子-vGPCR可以诱导内皮细胞中mTOR的活性，提示vGPCR通过直接和间接（旁分泌）机制调节mTOR。另外，我们发现雷帕霉素对vGPCR肉瘤发生的作用不依赖于表达vGPCR的细胞中mTOR的直接活化。相反，这些肿瘤对雷帕霉素治疗的高度敏感性可能部分归因于EC-vGPCR阐明的血管生成因子抑制相邻（旁观者）细胞中mTOR的旁分泌激活。总之，这些结果支持旁分泌转化机制在vGPCR肉瘤发生中的关键作用。

著录项

  • 作者

    Chaisuparat, Risa.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 138 p.
  • 总页数 138
  • 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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