Hsp90 inhibitors are efficacious against Kaposi Sarcoma by enhancing the degradation of the essential viral gene LANA, of the viral co-receptor EphA2 as well as other client proteins.
Hsp90 inhibitors are efficacious against Kaposi Sarcoma by enhancing the degradation of the essential viral gene LANA, of the viral co-receptor EphA2 as well as other client proteins.
复制标题
DOI：
10.1371/journal.ppat.1003048
复制
发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Dittmer DP
中科院分区：
文献类型：
--
作者：
Chen W;Sin SH;Wen KW;Damania B;Dittmer DP
热休克蛋白90（Hsp 90）抑制剂表现出抗人类癌症的活性。我们评估了一系列新的口服生物可利用的化学多样性Hsp 90抑制剂（PU-H71、AUY 922、BIIB 021、NVP-BEP 800）对卡波西肉瘤（KS）的作用。所有Hsp 90抑制剂在培养物中均表现出纳摩尔EC 50，AUY 922在KS异种移植模型中降低了肿瘤负荷。KS与KS相关疱疹病毒（KSHV）有关。我们鉴定了病毒潜伏相关核抗原（拉娜）作为Hsp 90的新客户蛋白，并证明Hsp 90抑制剂通过蛋白酶体降解降低拉娜的水平。这些Hsp 90抑制剂还下调EphA 2和肝配蛋白-B2蛋白水平。拉娜对于病毒维持是必需的，并且EphA 2最近已显示促进KSHV感染;这反过来又助长潜伏的持久性。此外，这两种分子都是KS肿瘤形成所需的，并且都响应于Hsp 90抑制剂而下调。这为在KSHV相关癌症和根除潜伏性KSHV储库中进行Hsp 90抑制剂的临床试验提供了理论基础。热休克蛋白，如Hsp 90，有助于蛋白质的折叠。它们似乎对维持癌细胞的生长至关重要。热休克蛋白90抑制剂在许多癌症的临床试验中，但结果喜忧参半，大概是因为这些蛋白质有许多客户。药物疗效和肿瘤类型变化的机制尚不清楚。在这里，我们表明，在卡波西肉瘤和原发性渗出性淋巴瘤的情况下，这是由卡波西肉瘤相关疱疹病毒（KSHV/HHV 8）引起的癌症，一种必需的病毒蛋白，拉娜，结合到HSP 90，是HSP 90的客户。不同的小分子Hsp 90抑制剂降低拉娜的表达。与此同时，它们降低了新发现的KSHV ephA 2、Akt、cdc 2和ephrin-B2的共受体的表达。由于需要拉娜来维持病毒潜伏在所有肿瘤细胞中，这是一个周期性地通过从头感染辅助的过程，因此这些抑制剂干扰病毒发病机制和体内肿瘤生长的基本组分。
Heat-shock protein 90 (Hsp90) inhibitors exhibit activity against human cancers. We evaluated a series of new, oral bioavailable, chemically diverse Hsp90 inhibitors (PU-H71, AUY922, BIIB021, NVP-BEP800) against Kaposi sarcoma (KS). All Hsp90 inhibitors exhibited nanomolar EC50 in culture and AUY922 reduced tumor burden in a xenograft model of KS. KS is associated with KS-associated herpesvirus (KSHV). We identified the viral latency associated nuclear antigen (LANA) as a novel client protein of Hsp90 and demonstrate that the Hsp90 inhibitors diminish the level of LANA through proteasomal degradation. These Hsp90 inhibitors also downregulated EphA2 and ephrin-B2 protein levels. LANA is essential for viral maintenance and EphA2 has recently been shown to facilitate KSHV infection; which in turn feeds latent persistence. Further, both molecules are required for KS tumor formation and both were downregulated in response to Hsp90 inhibitors. This provides a rationale for clinical testing of Hsp90 inhibitors in KSHV-associated cancers and in the eradication of latent KSHV reservoirs. Heat shock proteins, such as Hsp90, aid the folding of proteins. They seem to be essential to sustain the growth of cancer cells. Hsp90 inhibitors are in clinical trials for many cancers but with mixed results, presumably since these proteins have many clients. The mechanism for drug efficacy and tumor-type variation in responses is not understood. Here we show that in the case of Kaposi sarcoma and primary effusion lymphoma, which are cancers caused by Kaposi sarcoma associated herpesvirus (KSHV/HHV8) an essential viral protein, LANA, binds to Hsp90 and is a client of Hsp90. Different small molecule Hsp90 inhibitors reduce the expression of LANA. At the same time they reduce the expression of the newly discovered co-receptor of KSHV ephA2, of Akt, cdc2 and ephrin-B2. Since LANA is required to maintain the virus latent in all tumor cells, a process, which is periodically aided by de novo infection, these inhibitors interfere with essential components of viral pathogenesis and in vivo tumor growth.
登录
查看更多内容
DOI：
10.1073/pnas.1119592109
发表时间：
2012-05-08
影响因子：
11.1
作者：
Chakraborty, Sayan;Veettil, Mohanan Valiya;Chandran, Bala
通讯作者：
Chandran, Bala
影响因子：
4
作者：
Field, N;Low, W;Collins, M
通讯作者：
Collins, M
影响因子：
4.8
作者：
An, FQ;Compitello, N;Renne, R
通讯作者：
Renne, R
DOI：
10.1073/pnas.0903392106
发表时间：
2009-05-19
影响因子：
11.1
作者：
Caldas-Lopes, Eloisi;Cerchietti, Leandro;Chiosis, Gabriela
通讯作者：
Chiosis, Gabriela
影响因子：
3.8
作者：
Djokovic D;Trindade A;Gigante J;Badenes M;Silva L;Liu R;Li X;Gong M;Krasnoperov V;Gill PS;Duarte A
通讯作者：
Duarte A