Lamivudine, Doravirine, and Cabotegravir Downregulate the Expression of Human Endogenous Retroviruses (HERVs), Inhibit Cell Growth, and Reduce Invasive Capability in Melanoma Cell Lines

Abstract

This study explores the impact of antiretroviral administration on the expression of human endogenous retroviruses (HERVs), cell growth, and invasive capability of human melanoma cell lines in culture. We investigated three antiretrovirals—lamivudine, doravirine, and cabotegravir—in A375, FO-1, and SK-Mel-28, BRAF-mutated, and in MeWo, P53-mutated, melanoma cell lines. The findings indicate a general capability of these drugs to downregulate the expression of HERV-K Pol and Env genes and hinder cell viability, mobility, and colony formation capacity of melanoma cells. The antiretroviral drugs also demonstrate selectivity against malignant cells, sparing normal human epithelial melanocytes. The study reveals that the integrase inhibitor cabotegravir is particularly effective in inhibiting cell growth and invasion across different cell lines in comparison with lamivudine and doravirine, which are inhibitors of the viral reverse transcriptase enzyme. The investigation further delves into the molecular mechanisms underlying the observed effects, highlighting the potential induction of ferroptosis, apoptosis, and alterations in cell cycle regulatory proteins. Our findings showed cytostatic effects principally revealed in A375, and SK-Mel-28 cell lines through a downregulation of retinoblastoma protein phosphorylation and/or cyclin D1 expression. Signs of ferroptosis were detected in both A375 cells and FO-1 cells by a decrease in glutathione peroxidase 4 and ferritin expression, as well as by an increase in transferrin protein levels. Apoptosis was also detected in FO-1 and SK-Mel-28, but only with cabotegravir treatment. Moreover, we explored the expression and activity of the stimulator of interferon genes (STING) protein and its correlation with programmed death-ligand 1 (PD-L1) expression. Both the STING activity and PD-L1 expression were decreased, suggesting that the antiretroviral treatments may counteract the detrimental effects of PD-L1 expression activation through the STING/interferon pathway triggered by HERV-K. Finally, this study underscores the potential therapeutic significance of cabotegravir in melanoma treatment. The findings also raise the prospect of using antiretroviral drugs to downregulate PD-L1 expression, potentially enhancing the therapeutic responses of immune checkpoint inhibitors.

Beyond pathogens: the intriguing genetic legacy of endogenous retroviruses in host physiology

“…The studies on HERV-K and cancer then intensified and many other types of cancer were also associated with the K family, as melanoma, leukemia, prostate, colorectal, brain, etc ( Figure 1 ) ( Brodsky et al., 1993 ; Sauter et al., 1995 ; Büscher et al., 2005 ; Manca et al., 2022 ). The studies spanned from the mRNA measures and the utility of HERV-K transcripts quantification as biomarkers for progression ( Contreras-Galindo et al., 2008 ), to the antibody anti-HERVs detection and mechanisms of malignancy and potential interventions ( Li et al., 2022 ; Manca et al., 2022 ; Zanrè et al., 2024 ). Although HERV-K is still the most explored HERV in cancer studies ( Figure 1 ), other families were also implicated in tumorigenesis as well.…”

“…Wang and colleagues also described that HERV-LTRs containing p53 binding site are capable to promote the activation of downstream genes associated with p53 (Wang et al, 2007). Based on an aberrant activation expression of HERV-K among different breast cancer samples, Liang et al (2024) (Liu et al, 2023) analyzed 91 HERV-K loci and nearby genes, investigating their impact on the tumor microenvironment (TME). Among the host genes close to the HERVs, some emerged as key genes associated with poor breast cancer prognosis.…”