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

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]

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

• Tipo de documento: Artigo Científico
• Fonte: ONCOTARGET; v. 6, n. 40, p. 43016-43032, DEC 15 2015.
• Citações Web of Science: 24

Resumo

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)

• Processo FAPESP: 11/13807-4 - Avaliação das vias de sinalização WNT/beta-catenina e Sonic Hedgehog e interações com miRNAs em tumores adrenocorticais pediátricos
• Beneficiário: Sonir Roberto Rauber Antonini
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 07/58365-3 - Fisiopatologia e etiopatogenia molecular de doenças relacionadas aos eixos corticotrófico, somatotrófico e neurohipofisário
• Beneficiário: Margaret de Castro
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 11/10512-3 - Avaliação da via Wnt/{beta}-catenina em tumores adrenocorticais da criança
• Beneficiário: Letícia Ferro Leal
• Modalidade de apoio: Bolsas no Brasil - Doutorado