Human Endogenous Retrovirus Type K Promotes Proliferation and Confers Sensitivity to Antiretroviral Drugs in Merlin-Negative Schwannoma and Meningioma.
Cancer Res
; 82(2): 235-247, 2022 01 15.
Article
em En
| MEDLINE
| ID: mdl-34853069
ABSTRACT
Deficiency of the tumor suppressor Merlin causes development of schwannoma, meningioma, and ependymoma tumors, which can occur spontaneously or in the hereditary disease neurofibromatosis type 2 (NF2). Merlin mutations are also relevant in a variety of other tumors. Surgery and radiotherapy are current first-line treatments; however, tumors frequently recur with limited treatment options. Here, we use human Merlin-negative schwannoma and meningioma primary cells to investigate the involvement of the endogenous retrovirus HERV-K in tumor development. HERV-K proteins previously implicated in tumorigenesis were overexpressed in schwannoma and all meningioma grades, and disease-associated CRL4DCAF1 and YAP/TEAD pathways were implicated in this overexpression. In normal Schwann cells, ectopic overexpression of HERV-K Env increased proliferation and upregulated expression of c-Jun and pERK1/2, which are key components of known tumorigenic pathways in schwannoma, JNK/c-Jun, and RAS/RAF/MEK/ERK. Furthermore, FDA-approved retroviral protease inhibitors ritonavir, atazanavir, and lopinavir reduced proliferation of schwannoma and grade I meningioma cells. These results identify HERV-K as a critical regulator of progression in Merlin-deficient tumors and offer potential strategies for therapeutic intervention. SIGNIFICANCE:
The endogenous retrovirus HERV-K activates oncogenic signaling pathways and promotes proliferation of Merlin-deficient schwannomas and meningiomas, which can be targeted with antiretroviral drugs and TEAD inhibitors.
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
/
Tipos_de_cancer
/
Outros_tipos
Base de dados:
MEDLINE
Assunto principal:
Proteínas Virais
/
Retrovirus Endógenos
/
Neurofibromina 2
/
Antirretrovirais
/
Proliferação de Células
/
Neoplasias Meníngeas
/
Meningioma
/
Neurilemoma
Tipo de estudo:
Diagnostic_studies
Limite:
Humans
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Reino Unido