| Autor(es): |
Leal, Leticia F.
[1]
;
Bueno, Ana Carolina
[1]
;
Gomes, Debora C.
[1, 2]
;
Abduch, Rafael
[1]
;
de Castro, Margaret
[3]
;
Antonini, Sonir R.
[1]
Número total de Autores: 6
|
| Afiliação do(s) autor(es): | [1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pediat, Sao Paulo - Brazil
[2] Univ Fed Uberlandia, Sch Med, Dept Pediat, BR-38400 Uberlandia, MG - Brazil
[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Internal Med, Sao Paulo - Brazil
Número total de Afiliações: 3
|
Background: To date, there is no effective therapy for patients with advanced/metastatic adrenocortical cancer (ACC). The activation of the Wnt/beta-catenin signaling is frequent in ACC and this pathway is a promising therapeutic target. Aim: To investigate the effects of the inhibition of the Wnt/beta-catenin in ACC cells. Methods: Adrenal (NCI-H295 and Y1) and non-adrenal (HeLa) cell lines were treated with PNU-74654 (5-200 mu M) for 24-96 h to assess cell viability (MTS-based assay), apoptosis (Annexin V), expression/localization of beta-catenin (qPCR, immunofluorescence, immunocytochemistry and western blot), expression of beta-catenin target genes (qPCR and western blot), and adrenal steroidogenesis (radioimmunoassay, qPCR and western blot). Results: In NCI-H295 cells, PNU-74654 significantly decreased cell proliferation 96 h after treatment, increased early and late apoptosis, decreased nuclear beta-catenin accumulation, impaired CTNNB1/beta-catenin expression and increased beta-catenin target genes 48 h after treatment. No effects were observed on HeLa cells. In NCI-H295 cells, PNU-74654 decreased cortisol, testosterone and androstenedione secretion 24 and 48 h after treatment. Additionally, in NCI-H295 cells, PNU-74654 decreased SF1 and CYP21A2 mRNA expression as well as the protein levels of STAR and aldosterone synthase 48 h after treatment. In Y1 cells, PNU-74654 impaired corticosterone secretion 24 h after treatment but did not decrease cell viability. Conclusions: Blocking the Tcf/beta-catenin complex inhibits the Wnt/-beta-catenin signaling in adrenocortical tumor cells triggering increased apoptosis, decreased cell viability and impairment of adrenal steroidogenesis. These promising findings pave the way for further experiments inhibiting the Wnt/beta-catenin pathway in pre-clinical models of ACC. The inhibition of this pathway may become a promising adjuvant therapy for patients with ACC. (AU) |