Abstract
Ticks, very successful vectors and reservoirs of diverse viruses and other infectious agents, are able to counteract host defence mechanisms and wound healing processes to facilitate blood-feeding. Cutting the epidermis by the tick chelicerae and penetration of the hypostome into the dermis followed by feeding elicit a wound healing response, involving coagulation, inflammation, angiogenesis, synthesis of extracellular matrix and ground substances, as well as tissue remodelling. These repair processes of injured skin are coordinated by a wide array of cytokines, chemokines and growth factors. Tick salivary gland compounds, in addition to their vital anticoagulant and immunomodulatory functions, also possess significant anti-tumour properties and represent very promising sources of novel pharmaceuticals. Among life-threatening cancers, cervical carcinoma is still a high risk. Human transforming growth factor-beta 1 (huTGF-β1) inhibitors are significant in anti-cancer therapy. In this study, we investigated effects of salivary gland extracts (SGE) of females of two ixodid ticks, Dermacentor reticulatus (DR SGE) and Hyalomma anatolicum excavatum (HAE SGE), on signalling pathways triggered by huTGF-β1 in two cervical carcinoma cell lines, SiHa and HeLa, varying in their response to huTGF-β1. By dual luciferase reporter assay we monitored activation/inhibition of canonical SMAD or non-canonical signalling pathways in cells treated with huTGF-β1 and DR SGE/HAE SGE. Using specific monoclonal antibodies we tested effects of SGE on phosphorylation of ERK1/2 and/or AKT-1 molecules. We were the first to detect significant inhibition of huTGF-β1 induced signalling pathways, canonical as well as non-canonical, by DR and HAE SGE. Although the overall effects of both SGE on signalling pathways were similar, we revealed different patterns of effects of the two SGE on phosphorylation of the monitored signal transducers. Further investigations in this field are required.
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Abbreviations
- DR:
-
Dermacentor reticulatus females, tick
- ECM:
-
extracellular matrix
- ERK:
-
extracellular signal-regulated kinase
- FGF-2:
-
fibroblast growth factor 2
- HAE:
-
Hyalomma anatolicum excavatum females, tick
- HGF:
-
hepatocyte growth factor
- huTGF-β1:
-
human transforming growth factor beta 1
- JNK:
-
c-Jun N-terminal kinase
- MAPK:
-
mitogen-activated protein kinase
- PDGF:
-
platelet-derived growth factor
- PI3K:
-
phosphatidylinositol 3-kinase
- PKB/AKT:
-
protein kinase B
- SG:
-
salivary glands
- SGE:
-
salivary gland extract
- SMAD:
-
Sma and Mad proteins from Caenorhabditis elegans and Drosophila, respectively
- STAT:
-
signal transducers and activators of transcription
- TGF-β1:
-
transforming growth factor beta 1
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Acknowledgements
The study was supported by the Slovak Research and Development Agency (APVV-0737-12) and Slovak VEGA grants 2/0089/13. The authors wish to thank Dr. Valeria Hajnicka for useful suggestions and ideas that helped to initiate this work.
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All experiments involving laboratory animals were performed in accordance with the animal use protocol approved by the ethical committee of Biomedical Research Center of Slovak Academy of Sciences and the State Veterinary and Food Administration of the Slovak Republic (permit numbers 1335/12–221 and 292/16-221e).
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Holíková, V., Štibrániová, I., Bartíková, P. et al. Ixodid tick salivary gland extracts suppress human transforming growth factor-β1 triggered signalling pathways in cervical carcinoma cells. Biologia 73, 1109–1122 (2018). https://doi.org/10.2478/s11756-018-0129-z
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DOI: https://doi.org/10.2478/s11756-018-0129-z