Curry Christine L, Reed Laura L, Golde Todd E, Miele Lucio, Nickoloff Brian J, Foreman Kimberly E
Department of Pathology and Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL 60153-5385, USA.
Oncogene. 2005 Sep 22;24(42):6333-44. doi: 10.1038/sj.onc.1208783.
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.
卡波西肉瘤（KS）是HIV-1感染个体中常见的肿瘤，会导致严重的发病和死亡。尽管最近有进展，但这种潜在危及生命的肿瘤的发病机制仍不清楚，目前KS尚无治愈方法。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基本作用。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也就不足为奇了。在本报告中，我们证明，与KS细胞的前体内皮细胞相比，体内和体外KS肿瘤细胞中活化的Notch-1、-2和-4水平升高。通过荧光素酶报告基因检测以及Hes（Hairy/Enhancer of Split）-1和Hey（Hairy/Enhancer of Split related with YRPW）1（Notch途径的主要靶点）在KS细胞核中的定位，证实了Notch激活。使用阻断Notch激活的γ-分泌酶抑制剂（GSI和LY-411,575）进行的研究导致原代和永生化KS细胞凋亡。将GSI注射到小鼠已建立的KS细胞肿瘤中的类似研究表明，其具有生长抑制或肿瘤消退作用，其特征是在接受治疗的肿瘤而非对照肿瘤中出现凋亡。结果表明，KS细胞过度表达活化的Notch，Notch信号的中断会抑制KS细胞生长。因此，靶向Notch信号可能对KS患者具有治疗价值。
