BackgroundEndoretroviruses account for circa 8 % of all transposable elements found in the genome of humans and other animals. They represent a genetic footprint of ancestral germ-cell infections of exoviruses that is transmittable to the progeny by Mendelian segregation. Traces of human endogenous retroviruses are physiologically expressed in ovarial, testicular and placental tissues as well as in stem cells. In addition, a number of these fossil viral elements have also been related to carcinogenesis. However, a relation between endoretroviruses expression and chemoresistance has not been reported yet.MethodsTwenty colorectal carcinoma patient samples were scrutinized for HERV-WE1 and HERV-FRD1 endoretroviruses using immunohistochemical approaches. In order to search for differential expression of these elements in chemotherapy refractory cells, a resistant HCT8 colon carcinoma subline was developed by serial etoposide exposure. Endoretroviral elements were detected by immunocytochemical staining, qPCR and ELISA. IC50-values of antiviral and cytostatic drugs in HCT8 cells were determined by MTT proliferation assay. The antivirals-cytostatics interaction was evaluated by the isobologram method.ResultsIn this work, we show for the first time that HERV-WE1, HERV-FRD1, HERV-31, and HERV-V1 are a) simultaneously expressed in treatment-naïve colon carcinoma cells and b) upregulated after cytostatic exposure, suggesting that these retroviral elements are intimately related to chemotherapy resistance. We found a number of antiviral drugs to have cytotoxic activity and the ability to force the downregulation of HERV proteins in vitro. We also demonstrate that the use of different antiviral compounds alone or in combination with anticancer agents results in a synergistic antiproliferative effect and downregulation of different endoretroviral elements in highly chemotherapy-resistant colorectal tumor cells.ConclusionsEnhanced HERV-expression is associated with chemoresistance in colon carcinomas which can be overcome by antiviral drugs alone or in combination with anticancer drugs. Therefore, the introduction of antiviral compounds to the current chemotherapy regimens potentially improves patient outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-015-0199-5) contains supplementary material, which is available to authorized users.
Membrane targeting of the Calcineurin B-like (CBL) calcium sensor proteins through protein S-acylation is crucial for various processes in plants, like nutrient uptake, plant development, and response to abiotic and biotic stresses. Certain CBLs target specifically to the vacuolar membrane, but which factors contribute to this particular localization and to the lipid modification efficiency are not yet known. Here, we examined the structural features of the N-terminus of Arabidopsis thaliana CBL2 and show that the lipid-modified cysteines are integrated within a predicted amphipathic helix. Mutations of amino acids, which contribute to the formation of this specific domain, affect S-acylation efficiency, membrane binding and function of CBL2. Interestingly, overexpression of the protein S-acyl transferase (PAT) 10 can compensate for the binding deficiency of a CBL2 mutant variant, which harbours a helix breaker mutation. This indicates that helix formation is rather involved in the S-acylation mechanism and is less important for membrane binding. Moreover, the introduction of basic residues resulted in a partial shift of the protein from the vacuolar to the plasma membrane, indicating that the underrepresentation of positively charged amino acids contributes to the vacuolar targeting specificity. Overall, our data suggest that helix formation is potentially an initial step in the S-acylation process and provides a deeper understanding of the mechanistic interplay between PATs and tonoplast targeted CBLs.
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