Dolutegravir Inhibits Proliferation and Motility of BT-20 Tumor Cells Through Inhibition of Human Endogenous Retrovirus Type K

Abstract

Increasing evidence points to the role of endogenous retroviruses (ERVs) in driving cancer cell proliferation. The purpose of this study was to explore the possibility of repurposing antiretroviral agents to inhibit ERVs as a new approach to cancer treatment. We found that an integrase strand-transfer inhibitor, dolutegravir (DTG), effectively inhibited the proliferation of multiple cancer cell lines and its antiproliferative potency was positively correlated with the expression levels of the human endogenous retrovirus type K (HERV-K). DTG inhibited the expression of HERV-K in multiple human cancer cell lines and the mouse mammary tumor virus (MMTV) in the murine 4T1 mammary cancer cell line. We chose the fast-growing BT-20 cell line as a model to study the in vitro antiproliferative mechanisms of DTG. BT-20 cells overexpressing both HERV-K env and pol genes became more resistant to DTG than cells transduced with vector alone. Knockdown of HERV-K also increased DTG resistance of BT-20 cells. The antiproliferative effect of DTG correlated with enhanced expression of E-cadherin and reduction in cell motility and invasiveness. Surprisingly, DTG stimulated expression of the env gene of MMTV in vivo and promoted metastasis of 4T1 tumor cells to the lungs. Taken together, our data support the role of ERVs in tumor development and encourage the further search for antiretroviral agents to treat malignancies in which ERVs are active.

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“…In support of this hypothesis, Perna et al indicated the migrationsuppressing effect of different anti-HIV drugs via increased expression of E-cadherin in ovarian cancer cell lines after treatment [47]. Another investigation supported the role of dolutegravir against migration and invasion in BT-20 cell lines through enhanced expression of E-cadherin [48]. Our findings consistently demonstrate that treatment of CT-26 cancer cells with lopinavir/ritonavir resulted in a significant rise in the mRNA expression of E-cadherin.…”

Comprehensive analysis of the progression mechanisms of CRPC and its inhibitor discovery based on machine learning algorithms

“…This binding event prevents the transfer of viral cDNA into the host DNA, thereby effectively inhibiting HIV-1 replication ( Hare et al, 2011 ). Recently, however, it has been reported that Dolutegravir may have anticancer effects by inhibiting the expression of human endogenous retrovirus type K (HERV-K) in various cancer cells ( Li et al, 2022 ). Our study has shown that Dolutegravir may also have anticancer effects by specifically binding to the CKS2 target in CRPC cells.…”

Development of human endogenous retrovirus type K‐ related treatments for human diseases

“…Recently, Li et al, reported that an integrase strand‐transfer inhibitor, Dolutegravir (DTG), effectively inhibited the proliferation of multiple cancer cell lines 32 . Furthermore, the antiproliferative potency of DTG correlated positively with the expression levels of HERV‐K.…”

“…Reduce proliferation of schwannoma and meningioma cells, through inhibition of HERV-K PR [31] The integrase inhibitor DTG Inhibit the proliferation of cancer cells, through repression of HERV-K expression [32] The integrase inhibitor Raltegravir Block HERV-K infection and production [26] The inhibitor of MEK, PD98059 or CDK4, 219476…”