Inhibition of KSHV-infected primary effusion lymphomas in NOD/SCID mice by gamma-secretase inhibitor.
Inhibition of KSHV-infected primary effusion lymphomas in NOD/SCID mice by gamma-secretase inhibitor.
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DOI：
10.4161/cbt.8.22.9743
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发表时间：
2009-11
影响因子：
3.6
通讯作者：
Robertson ES
中科院分区：
文献类型：
--
作者：
Lan K;Murakami M;Bajaj B;Kaul R;He Z;Gan R;Feldman M;Robertson ES
原发性渗出性淋巴瘤（PEL）是艾滋病患者常见的恶性肿瘤，与卡波西肉瘤相关疱疹病毒（KSHV）密切相关。以前，我们表明，KSHV潜伏相关核抗原（拉娜）稳定细胞内激活的Notch 1（ICN）参与维持KSHV感染的PEL细胞在体外的恶性表型。γ-分泌酶抑制剂（GSI）特异性阻断ICN的产生，在体外减缓KSHV感染的PEL细胞系BCBL 1、BC 3以及JSC 1的增殖。在这项研究中，我们扩展了这些研究，以探索通过GSI操纵Notch信号传导将阻止体内PEL肿瘤生长的可能性。我们观察到KSHV感染的PEL的肿瘤发生在GSI处理的携带PEL细胞系的SCID小鼠中显著延迟。我们还发现GSI处理导致由异种移植的KSHV阳性PEL细胞系产生的肿瘤的坏死以及凋亡。相反，GSI对携带BJAB细胞的小鼠没有影响，BJAB细胞是一种KSHV阴性伯基特淋巴瘤细胞系，其中ICN水平可忽略不计。我们的研究提供了进一步的证据表明，靶向下调异常Notch信号传导对KSHV相关的原发性渗出性淋巴瘤具有治疗潜力。
Primary effusion lymphoma (PEL) is a common cancer in AIDS patients closely associated with Kaposi’s sarcoma-associated herpesvirus (KSHV). Previously, we showed that KSHV latency associated nuclear antigen (LANA) stabilizes intracellular activated Notch1 (ICN) involved in maintenance of the malignant phenotype of KSHV infected PEL cells in vitro. The γ-secretase inhibitor (GSI) which specifically blocks the production of ICN slows down the proliferation of the KSHV infected PEL cell lines BCBL1, BC3 as well as JSC1 in vitro. In this study, we extended these studies to explore the possibility that manipulation of the Notch signaling by GSI would prevent the growth of the PEL tumors in vivo. We observed that the onset of tumorigenesis of KSHV infected PELs was significantly delayed in GSI treated SCID mice harboring the PEL cell lines. We also found that GSI treatment resulted in necrosis as well as apoptosis in tumors generated by the xenotransplanted KSHV positive PEL cell lines. In contrast, GSI had no effect on mice harboring BJAB cells, a KSHV negative Burkitt’s lymphoma cell line where ICN levels were negligible. Our study provides further evidence to suggest that targeted downregulation of abnormal Notch signaling has therapeutic potential for KSHV related primary effusion lymphomas.
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影响因子：
10.5
作者：
JHAPPAN, C;GALLAHAN, D;CALLAHAN, R
通讯作者：
CALLAHAN, R
影响因子：
8
作者：
Curry, CL;Reed, LL;Foreman, KE
通讯作者：
Foreman, KE
影响因子：
5.4
作者：
Kaul, Rajeev;Murakami, Masanao;Robertson, Erle S.
通讯作者：
Robertson, Erle S.
DOI：
10.1073/pnas.0703508104
发表时间：
2007-10-09
影响因子：
11.1
作者：
Lan, Ke;Verma, Subhash C.;Robertson, Erle S.
通讯作者：
Robertson, Erle S.
影响因子：
5.4
作者：
Hyun, TS;Subramanian, CA;Robertson, ES
通讯作者：
Robertson, ES