Effects of Ritonavir on HHV-8 vGPCR signaling and tumorigenesis

描述（由申请方提供）：人疱疹病毒8型（HHV-8）是卡波西肉瘤（KS）的主要病原体，编码vGPCR，vGPCR是人IL-8受体的同源物，也是G蛋白偶联受体（GPCR）家族的成员。由HHV-8开放阅读框74编码的vGPCR激活包括NF κ B和NF- AT的转录因子，并诱导由这些因子调节的细胞因子和细胞表面粘附分子的表达。在Tg小鼠中表达vGPCR导致KS样肿瘤，并且我们已经从这些肿瘤中的一种获得了保留vGPCR表达和裸鼠致瘤性的细胞系。我们以前已经证明利托那韦，一种用于治疗HIV感染的蛋白酶抑制剂，抑制NF κ B的激活。初步研究表明，利托那韦也抑制NF-AT激活。利托那韦抑制裸鼠异种移植模型中使用人KS衍生的HHV-8阴性细胞系的肿瘤发生。我们建议表征利托那韦抑制vGPCR介导的信号传导和肿瘤发生的机制。这些研究将包括鉴定利托那韦抑制NF κ B和NF-AT活化的信号通路，并确定利托那韦抑制NF κ B和/或NF-AT活化是否抑制裸鼠中vGPCR依赖性肿瘤发生。这些研究将显示利托那韦是否在体外和体内阻断HHV-8 vGPCR的活性，以及它是否具有独立于其抗逆转录病毒活性的抗KS活性。因此，这些结果可能为开发KS的新治疗替代方案提供理论基础。这些发现可能对其他癌症具有更普遍的适用性。

DESCRIPTION (provided by applicant): Human herpesvirus 8 (HHV-8), the primary etiologic agent of Kaposi's sarcoma (KS), encodes vGPCR, a homologue of the human IL-8 receptor and a member of the G protein coupled receptor (GPCR) family. vGPCR, encoded by HHV-8 open reading frame 74, activates transcription factors including NFkappaB and NF- AT and induces expression of cytokines and cell surface adhesion molecules regulated by these factors. Expression of vGPCR in Tg mice causes KS-like tumors, and we have derived a cell line from one of these tumors that retains expression of vGPCR and tumorigenicity in nude mice. We have previously shown that ritonavir, a protease inhibitor used to treat HIV infection, inhibits NFkappaB activation. Preliminary studies suggest that ritonavir also inhibits NF-AT activation. Ritonavir inhibits tumorigenesis in a nude mouse xenotransplant model using human KS-derived HHV-8-negative cell lines. We propose characterizing the mechanisms of inhibition by ritonavir of vGPCR-mediated signaling and tumorigenesis. These studies will include identifying the signaling pathways through which ritonavir inhibits NFkappaB and NF-AT activation and determining whether inhibition of NFkappaB and/or NF-AT activation by ritonavir inhibits vGPCR-dependent tumorigenesis in nude mice. These studies will show whether ritonavir blocks the activities of HHV-8 vGPCR in vitro and in vivo and whether it has an anti-KS activity independent of its anti-retro viral activity. Consequently, the results may provide a rationale for developing new therapeutic alternatives for KS. The findings could have a more general applicability to other cancers.