Enhanced antitumoral activity of TLR7 agonists via activation of human endogenous retroviruses by HDAC inhibitors.
Enhanced antitumoral activity of TLR7 agonists via activation of human endogenous retroviruses by HDAC inhibitors.
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DOI：
10.1038/s42003-021-01800-3
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发表时间：
2021-03-03
影响因子：
5.9
通讯作者：
Strumberg D
中科院分区：
文献类型：
--
作者：
Díaz-Carballo D;Saka S;Acikelli AH;Homp E;Erwes J;Demmig R;Klein J;Schröer K;Malak S;D'Souza F;Noa-Bolaño A;Menze S;Pano E;Andrioff S;Teipel M;Dammann P;Klein D;Nasreen A;Tannapfel A;Grandi N;Tramontano E;Ochsenfarth C;Strumberg D
在这项工作中，我们报告说，“休克和杀死”，一种治疗方法，旨在消除潜伏的艾滋病毒从细胞库，是推断癌症治疗。这是基于观察到恶性细胞表达一系列人内源性逆转录病毒元件（HERV），其可以通过HDAC抑制剂在转录上增强。内逆转录病毒基因HERV-V2编码包膜蛋白，其类似于合胞素。它在暴露于HDAC抑制剂后显著过表达，并且可以通过同时应用TLR 7/8激动剂有效靶向，从而触发内在凋亡。我们证明这种协同细胞毒性作用伴随着TLR 7/8-NFκB、Akt/PK B和Ras-MEK-ERK信号通路的功能性破坏。CRISPR/Cas9消融TLR 7和HERV-V1/V2显著减少了细胞凋亡，证明了这些元件在驱动细胞死亡中的关键作用。这种新方法的有效性在卵巢肿瘤异种移植研究中得到了证实，为未来的癌症治疗开辟了一条有希望的途径。Díaz-Carballo等人发现HDAC抑制剂诱导卵巢癌细胞中人内源性逆转录病毒包膜基因的表达，并且Toll样受体（TLR）7/8激动剂与HDAC抑制剂协同作用触发癌细胞凋亡。该组合还减少了卵巢肿瘤异种移植物的生长，为未来的治疗提供了潜在的理论基础。
In this work, we are reporting that “Shock and Kill”, a therapeutic approach designed to eliminate latent HIV from cell reservoirs, is extrapolatable to cancer therapy. This is based on the observation that malignant cells express a spectrum of human endogenous retroviral elements (HERVs) which can be transcriptionally boosted by HDAC inhibitors. The endoretroviral gene HERV-V2 codes for an envelope protein, which resembles syncytins. It is significantly overexpressed upon exposure to HDAC inhibitors and can be effectively targeted by simultaneous application of TLR7/8 agonists, triggering intrinsic apoptosis. We demonstrated that this synergistic cytotoxic effect was accompanied by the functional disruption of the TLR7/8-NFκB, Akt/PKB, and Ras-MEK-ERK signalling pathways. CRISPR/Cas9 ablation of TLR7 and HERV-V1/V2 curtailed apoptosis significantly, proving the pivotal role of these elements in driving cell death. The effectiveness of this new approach was confirmed in ovarian tumour xenograft studies, revealing a promising avenue for future cancer therapies. Díaz-Carballo et al. find that HDAC inhibitors induces the expression of human endogenous retrovirus envelope genes in ovarian cancer cells, and that Toll-like receptor (TLR) 7/8 agonists act synergistically with HDAC inhibitors in triggering cancer cell apoptosis. The combination also reduces growth of ovarian tumour xenografts, providing a potential rationale for future therapies.
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影响因子：
6.4
作者：
Bai, Dong;Ueno, Lynn;Vogt, Peter K.
通讯作者：
Vogt, Peter K.
影响因子：
7.4
作者：
Josephs SF;Ichim TE;Prince SM;Kesari S;Marincola FM;Escobedo AR;Jafri A
通讯作者：
Jafri A
影响因子：
5.6
作者：
Divsalar, Donya Naz;Simoben, Conrad Veranso;Tietjen, Ian
通讯作者：
Tietjen, Ian
影响因子：
1.5
作者：
Jern, P;Lindeskog, M;Blomberg, J
通讯作者：
Blomberg, J
Toll 样受体 7 激动剂以延长给药方案皮下注射，用于治疗经过严格预处理的复发性乳腺癌、卵巢癌和宫颈癌。
DOI：
10.1007/s00262-010-0914-1
发表时间：
2010-12
期刊：
Cancer immunology, immunotherapy : CII
影响因子：
--
作者：
Geller MA;Cooley S;Argenta PA;Downs LS;Carson LF;Judson PL;Ghebre R;Weigel B;Panoskaltsis-Mortari A;Curtsinger J;Miller JS
通讯作者：
Miller JS