Hsp90 inhibitors block outgrowth of EBV-infected malignant cells in vitro and in vivo through an EBNA1-dependent mechanism

Xiaoping Sun; Elizabeth A. Barlow; Shidong Ma; Stacy R. Hagemeier; Sarah J. Duellman; Richard R. Burgess; Judy Tellam; Rajiv Khanna; Shannon C. Kenney

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Hsp90 inhibitors block outgrowth of EBV-infected malignant cells in vitro and in vivo through an EBNA1-dependent mechanism

机译：Hsp90抑制剂通过EBNA1依赖性机制在体外和体内阻断EBV感染的恶性细胞的生长

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EBV causes infectious mononucleosis and is associated with certain malignancies. EBV nuclear antigen 1 (EBNA1) mediates EBV genome replication, partition, and transcription, and is essential for persistence of the viral genome in host cells. Here we demonstrate that Hsp90 inhibitors decrease EBNA1 expression and translation, and that this effect requires the Gly-Ala repeat domain of EBNA1. Hsp90 inhibitors induce the death of established, EBV-transformed lym-phoblastoid cell lines at doses nontoxic to normal cells, and this effect is substantially reversed when lymphoblastoid cell lines are stably infected with a retrovirus expressing a functional EBNA1 mutant lacking the Gly-Ala repeats. Hsp90 inhibitors prevent EBV transformation of primary B cells, and strongly inhibit the growth of EBV-induced lymphoproliferative disease in SCID mice. These results suggest that Hsp90 inhibitors may be particularly effective for treating EBV-induced diseases requiring the continued presence of the viral genome.

机译：EBV引起传染性单核细胞增多症，并与某些恶性肿瘤相关。 EBV核抗原1（EBNA1）介导EBV基因组的复制，分配和转录，对于病毒基因组在宿主细胞中的持久性至关重要。在这里，我们证明了Hsp90抑制剂会降低EBNA1的表达和翻译，并且这种作用需要EBNA1的Gly-Ala重复结构域。 Hsp90抑制剂以对正常细胞无毒的剂量诱导已建立的，经EBV转化的淋巴-成纤维细胞系的死亡，当淋巴母细胞系被表达缺乏Gly-Ala重复序列的功能性EBNA1突变的逆转录病毒稳定感染时，这种作用基本上可以逆转。 Hsp90抑制剂可防止EBV转化原代B细胞，并在SCID小鼠中强烈抑制EBV诱导的淋巴增生性疾病的生长。这些结果表明，Hsp90抑制剂对于需要持续存在病毒基因组的EBV诱导的疾病可能特别有效。

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《Proceedings of the National Academy of Sciences of the United States of America》 |2010年第7期|3146-3151|共6页
作者
Xiaoping Sun; Elizabeth A. Barlow; Shidong Ma; Stacy R. Hagemeier; Sarah J. Duellman; Richard R. Burgess; Judy Tellam; Rajiv Khanna; Shannon C. Kenney;
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作者单位

Departments of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison,WI 53706;

rnDepartments of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison,WI 53706;

rnDepartments of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison,WI 53706;

rnDepartments of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison,WI 53706;

rnDepartments of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison,WI 53706;

rnDepartments of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison,WI 53706;

rnDivision of Infectious Diseases and Immunology, Australian Centre for Vaccine Development and Tumour Immunology Laboratory, Clive Berghofer Cancer Research Centre, Queensland Institute of Medical Research, Brisbane, QLD 4006, Australia;

rnDivision of Infectious Diseases and Immunology, Australian Centre for Vaccine Development and Tumour Immunology Laboratory, Clive Berghofer Cancer Research Centre, Queensland Institute of Medical Research, Brisbane, QLD 4006, Australia;

rnDepartments of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison,WI 53706 Departments of Medicine, McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, Madison,Wl 53706;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种 eng
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关键词
Epstein-Barr virus; 17-DMAG; 17-AAG; geldanamycin; translation;

机译：爱泼斯坦-巴尔病毒;17-DMAG;17-AAG;格尔德霉素翻译;

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6. Hsp90 inhibitors block outgrowth of EBV-infected malignant cells in vitro and in vivo through an EBNA1-dependent mechanism [O] . Xiaoping Sun, Elizabeth A. Barlow, Shidong Ma, 2010

机译：Hsp90抑制剂通过EBNA1依赖性机制在体外和体内阻断EBV感染的恶性细胞的生长
7. Hsp90 inhibitors block outgrowth of EBV-infected malignant cells in vitro and in vivo through an EBNA1-dependent mechanism [O] . Sun, Xiaoping, Barlow, Elizabeth A., Ma, Shidong, 2010

机译：Hsp90抑制剂通过EBNA1依赖性机制在体外和体内阻断EBV感染的恶性细胞的生长
8. Development of Tethered Hsp90 Inhibitors Carrying Radioiodinated Probes to Specifically Discriminate and Kill Malignant Breast Tumor Cells. [R] . Zalutsky , M. R., Haystead, T. 2017

机译：携带放射性碘标记物的系留Hsp90抑制剂的开发，以特异性鉴别和杀死恶性乳腺肿瘤细胞。

Hsp90 inhibitors block outgrowth of EBV-infected malignant cells in vitro and in vivo through an EBNA1-dependent mechanism

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