Enhanced antitumoral activity of TLR7 agonists via activation of human endogenous retroviruses by HDAC inhibitors

被引：19

作者：

Diaz-Carballo, David ^{[1
]}

Saka, Sahitya ^{[1
]}

Acikelli, Ali H. ^{[1
]}

Homp, Ekaterina ^{[1
]}

Erwes, Julia ^{[1
]}

Demmig, Rebecca ^{[1
]}

Klein, Jacqueline ^{[1
]}

Schroeer, Katrin ^{[1
]}

Malak, Sascha ^{[1
]}

D'Souza, Flevy ^{[1
]}

Noa-Bolano, Adrien ^{[1
]}

Menze, Saskia ^{[1
]}

Pano, Emilio ^{[1
]}

Andrioff, Swetlana ^{[1
]}

Teipel, Marc ^{[1
]}

Dammann, Philip ^{[2
]}

Klein, Diana ^{[3
]}

Nasreen, Amber ^{[4
]}

Tannapfel, Andrea ^{[5
]}

Grandi, Nicole ^{[6
]}

Tramontano, Enzo ^{[6
]}

Ochsenfarth, Crista ^{[7
]}

Strumberg, Dirk ^{[1
]}

机构：

[1] Ruhr Univ Bochum, Marien Hosp Herne, Inst Mol Oncol & Expt Therapeut, Fac Med,Dept Haematol & Oncol, Herne, Germany

[2] Univ Duisburg Essen, Univ Hosp Essen, Cent Anim Lab, Essen, Germany

[3] Univ Duisburg Essen, Univ Hosp Essen, Inst Cell Biol, Canc Res, Essen, Germany

[4] Ruhr Univ Bochum, Med Sch, Marien Hosp Herne, Visceral Surg Dept, Herne, Germany

[5] Ruhr Univ Bochum, Inst Pathol, Bochum, Germany

[6] Univ Cagliari, Dept Life & Environm Sci, Monserrato, Italy

[7] Ruhr Univ Bochum, Marien Hosp Herne, Med Sch, Dept Anesthesia Intens Care Pain & Palliat Med, Herne, Germany

来源：

COMMUNICATIONS BIOLOGY | 2021年 / 4卷 / 01期

关键词：

D O I：

10.1038/s42003-021-01800-3

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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-NF kappa B, 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. Diaz-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.

引用

页数：16

共 57 条

[1] Toll-like receptor 7 agonist, Imiquimod, inhibits oral squamous carcinoma cells through apoptosis and necrosis [J].