Advanced search
Start date
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Inhibition of the Tcf/beta-catenin complex increases apoptosis and impairs adrenocortical tumor cell proliferation and adrenal steroidogenesis

Full text
Leal, Leticia F. [1] ; Bueno, Ana Carolina [1] ; Gomes, Debora C. [1, 2] ; Abduch, Rafael [1] ; de Castro, Margaret [3] ; Antonini, Sonir R. [1]
Total Authors: 6
[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
Total Affiliations: 3
Document type: Journal article
Source: ONCOTARGET; v. 6, n. 40, p. 43016-43032, DEC 15 2015.
Web of Science Citations: 24

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)

FAPESP's process: 11/13807-4 - Analysis of the WNT and Sonic Hedgehog pathways in childhood adrenocortical tumors and its relationship with miRNAs
Grantee:Sonir Roberto Rauber Antonini
Support Opportunities: Regular Research Grants
FAPESP's process: 11/10512-3 - Analysis of Wnt/{beta}-catenin pathway in childhood adrencortical tumors
Grantee:Letícia Ferro Leal
Support Opportunities: Scholarships in Brazil - Doctorate