Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells
Gamma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi's sarcoma tumor cells
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DOI：
10.1038/sj.onc.1208783
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发表时间：
2005-09-22
期刊：
影响因子：
8
通讯作者：
Foreman, KE
中科院分区：
文献类型：
--
作者：
Curry, CL;Reed, LL;Foreman, KE
卡波西氏肉瘤（KS）是一种常见的肿瘤在HIV-1感染的个人造成显着的发病率和死亡率。尽管最近的进展，这种可能危及生命的肿瘤的发病机制仍然不清楚，目前没有治愈KS。已知Notch蛋白在包括增殖、分化和凋亡在内的细胞命运决定中起重要作用。因此，Notch蛋白与肿瘤发生有关，并且根据细胞环境似乎作为癌基因或肿瘤抑制蛋白发挥作用，这并不奇怪。在这份报告中，我们证明了在体内和体外KS肿瘤细胞中激活的Notch-1，-2和-4水平升高，与内皮细胞相比，内皮细胞是KS细胞的前体。通过荧光素酶报告基因测定和KS细胞核中Hes（Hairy/Enhancer of Split）-1和Hey（Hairy/Enhancer of Split related with YRPW）1（Notch途径的主要靶标）的定位来确认Notch激活。使用阻断Notch活化的γ-分泌酶抑制剂（GSI和LY-411，575）的研究导致原代和永生化KS细胞的凋亡。将GSI注射到小鼠的已建立的KS细胞肿瘤中的类似研究证明了生长抑制或肿瘤消退，其特征在于在治疗的肿瘤中而不是对照肿瘤中的细胞凋亡。结果表明KS细胞过表达活化的Notch，并且Notch信号传导的中断抑制KS细胞生长。因此，靶向Notch信号传导可能在KS患者中具有治疗价值。
Kaposi's sarcoma (KS) is a common neoplasm in HIV-1-infected individuals causing significant morbidity and mortality. Despite recent advances, the pathogenesis of this potentially life-threatening neoplasm remains unclear, and there is currently no cure for KS. Notch proteins are known to play a fundamental role in cell fate decisions including proliferation, differentiation, and apoptosis. It is, therefore, not surprising that Notch proteins have been implicated in tumorigenesis and appear to function as either oncogenes or tumor suppressor proteins depending on cellular context. In this report, we demonstrate elevated levels of activated Notch-1, -2, and -4 in KS tumor cells in vivo and in vitro compared to endothelial cells, the precursor of the KS cell. Notch activation was confirmed through luciferase reporter assays and localization of Hes (Hairy/Enhancer of Split)-1 and Hey (Hairy/Enhancer of Split related with YRPW)1 (primary targets of the Notch pathway) in KS cell nuclei. Studies using gamma-secretase inhibitors (GSI and LY- 411,575), which block Notch activation, resulted in apoptosis in primary and immortalized KS cells. Similar studies injecting GSI into established KS cell tumors on mice demonstrated growth inhibition or tumor regression that was characterized by apoptosis in treated, but not control tumors. The results indicate that KS cells overexpress activated Notch and interruption of Notch signaling inhibits KS cell growth. Thus, targeting Notch signaling may be of therapeutic value in KS patients.