Anti-Müllerian hormone concentration regulates activin receptor-like kinase-2/3 expression levels with opposing effects on ovarian cancer cell survival.
Int J Oncol
; 59(1)2021 Jul.
Article
em En
| MEDLINE
| ID: mdl-34013359
ABSTRACT
AntiMüllerian hormone (AMH) type II receptor (AMHRII) and the AMH/AMHRII signaling pathway are potential therapeutic targets in ovarian carcinoma. Conversely, the role of the three AMH type I receptors (AMHRIs), namely activin receptorlike kinase (ALK)2, ALK3 and ALK6, in ovarian cancer remains to be clarified. To determine the respective roles of these three AMHRIs, the present study used four ovarian cancer cell lines (COV434AMHRII, SKOV3AMHRII, OVCAR8, KGN) and primary cells isolated from tumor ascites from patients with ovarian cancer. The results demonstrated that ALK2 and ALK3 may be the two main AMHRIs involved in AMH signaling at physiological endogenous and supraphysiological exogenous AMH concentrations, respectively. Supraphysiological AMH concentrations (25 nM recombinant AMH) were associated with apoptosis in all four cell lines and decreased clonogenic survival in COV434AMHRII and SKOV3AMHRII cells. These biological effects were induced via ALK3 recruitment by AMHRII, as ALK3AMHRII dimerization was favored at increasing AMH concentrations. By contrast, ALK2 was associated with AMHRII at physiological endogenous concentrations of AMH (10 pM). Based on these results, tetravalent IgG1like bispecific antibodies (BsAbs) against AMHRII and ALK2, and against AMHRII and ALK3 were designed and evaluated. In vivo, COV434AMHRII tumor cell xenograft growth was significantly reduced in all BsAbtreated groups compared with that in the vehicle group (P=0.018 for BsAb 12G43D7; P=0.001 for all other BsAbs). However, the growth of COV434AMHRII tumor cell xenografts was slower in mice treated with the antiAMRIIALK2 BsAb 12G42F9 compared with that in animals that received a control BsAb that targeted AMHRII and CD5 (P=0.048). These results provide new insights into type I receptor specificity in AMH signaling pathways and may lead to an innovative therapeutic approach to modulate AMH signaling using antiAMHRII/antiAMHRI BsAbs.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
/
Receptores de Ativinas Tipo I
/
Receptores de Proteínas Morfogenéticas Ósseas Tipo I
/
Hormônio Antimülleriano
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Int J Oncol
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
França