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(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

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Author(s):
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
Affiliation:
[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
Abstract

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: 11/10512-3 - Analysis of Wnt/{beta}-catenin pathway in childhood adrencortical tumors
Grantee:Letícia Ferro Leal
Support type: Scholarships in Brazil - Doctorate
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 type: Regular Research Grants