Abstract
Abstract Background: HERVs account for ca. 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. Methods: Twenty colorectal carcinoma patient samples were analyzed for HERV-WE1 and HERV-FRD1 endoretroviruses using immunohistochemical approaches. In addition, to examine for differential expression of HERVs 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. Results: In 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 from patients and b) upregulated after cytostatic exposure in colon-cancer cell lines, suggesting that these retroviral elements are intimately related to chemotherapy resistance. A number of antiviral drugs showed not only cytotoxic activity but also downregulation of HERV proteins in vitro. We also demonstrate that the use of different antiviral compounds alone or in combination with anticancer agents present synergistic antiproliferative activity and downregulation of different endoretroviral elements in highly chemotherapy-resistant colorectal tumor cells. Conclusions: Enhanced HERV-expression is associated with chemo-resistance in colon carcinoma cells which can be repressed by antiviral drugs alone or in combination with anticancer drugs. Therefore, the introduction of antiviral compounds to antiproliferative chemotherapy regimens potentially improves patient outcomes. Citation Format: David Diaz-Carballo. Overexpressing human endogenous retroviral elements (HERVs) in chemorefractory colorectal adenocarcinoma cells are repressed by antiviral drugs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1842.
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