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

Autor: Díaz-Carballo D; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany. david.diaz-carballo@marienhospital-herne.de., Saka S; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., Acikelli AH; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., Homp E; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., Erwes J; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., Demmig R; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., Klein J; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., Schröer K; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., Malak S; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., D'Souza F; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., Noa-Bolaño A; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., Menze S; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., Pano E; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., Andrioff S; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., Teipel M; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany., Dammann P; Central Animal Laboratory, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Klein D; Institute of Cell Biology, Cancer Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Nasreen A; Visceral Surgery Department, Marien Hospital Herne, Ruhr University Bochum Medical School, Herne, Germany., Tannapfel A; Institute of Pathology, Ruhr University Bochum, Bochum, Germany., Grandi N; Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Italy., Tramontano E; Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Italy., Ochsenfarth C; Department of Anesthesia, Intensive Care, Pain and Palliative Medicine, Marien Hospital Herne, Ruhr-University Bochum Medical School, Herne, Germany., Strumberg D; Ruhr University Bochum, Faculty of Medicine, Department of Haematology and Oncology, Institute of Molecular Oncology and Experimental Therapeutics, Marien Hospital Herne, Herne, Germany.
Jazyk: angličtina
Zdroj: Communications biology [Commun Biol] 2021 Mar 03; Vol. 4 (1), pp. 276. Date of Electronic Publication: 2021 Mar 03.
DOI: 10.1038/s42003-021-01800-3
Abstrakt: 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.
Databáze: MEDLINE
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