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

Leal, Letícia Ferro; Bueno, Ana Carolina; Gomes, Débora Cristiane; Abduch, Rafael Haikal; Castro, Margaret de; Antonini, Sonir Roberto Rauber

doi:10.18632/oncotarget.5513

Cited by 64 publications

(75 citation statements)

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“…Thus, this cell line is a good model to be used to evaluate the effect of the pharmacological modulation of the Wnt/beta-catenin pathway in vitro . Interestingly, we found that inhibition of the Wnt/beta-catenin pathway decreased YAP1 protein expression in parallel to the reduction of beta-catenin expression [21]. Thus, our data support that YAP1 is a Wnt/beta-catenin target in adrenocortical cells.…”

Section: Discussionsupporting

confidence: 74%

Unraveling the expression of the oncogene YAP1, a Wnt/beta-catenin target, in adrenocortical tumors and its association with poor outcome in pediatric patients

et al. 2016

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BackgroundOverexpression of the oncogene yes-associated-protein-1 (YAP1) is associated with increased cell proliferation in human cancers. YAP1 is a potential target of the Wnt/beta-catenin pathway, which plays an important role in adrenocortical tumors (ACT). The role of YAP1 in adrenocortical tumorigenesis has not been assessed.Aims: To evaluate YAP1 expression in normal adrenals and pediatric ACT and its association with disease outcome. To investigate the interaction between YAP1 and the Wnt/beta-catenin pathway in adrenocortical cells.ResultsStrong YAP1 staining was present in fetal adrenals and pediatric ACT but weak in postnatal adrenals. In pediatric ACT, YAP1 mRNA overexpression was associated with death, recurrent/metastatic disease and lower overall survival. The inhibition of the Wnt/beta-catenin pathway increased YAP1 mRNA expression. siYAP1 increased CTNNB1/beta-catenin expression and nuclear staining regardless of DLV2, moreover, it decreased cell growth and impaired cell migration.Materials and MethodsWe assessed in 42 pediatric ACT samples the YAP1 protein expression by immunohistochemistry and mRNA expression by RT-qPCR and analyzed their association with outcome. As controls, we resort 32 fetal and postnatal normal adrenals for IHC and 10 normal adrenal cortices for RT-qPCR. The interaction between YAP1 and the Wnt/beta-catenin pathway was assessed in NCI-H295 adrenocortical cells by inhibiting the TCF/beta-catenin complex and by knocking down YAP1.ConclusionYAP1 overexpression is a marker of poor prognosis for pediatric patients with ACT. In adrenocortical cells, there is a close crosstalk between YAP1 and Wnt/beta-catenin. These data open the possibility of future molecular therapies targeting Hippo/YAP1 signaling to treat advanced ACT.

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Section: Discussionsupporting

confidence: 74%

Unraveling the expression of the oncogene YAP1, a Wnt/beta-catenin target, in adrenocortical tumors and its association with poor outcome in pediatric patients

et al. 2016

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“…Interestingly, NCI-H295 lacks TP53 p.R337H, but presents other mutations affecting p53 functions (Sampaoli et al 2012, Leal et al 2015, which also could be related to reduced effectiveness of therapies, such as anti-IGF1R.…”

Section: Discussionmentioning

confidence: 99%

IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis

Lira¹,

Fedatto²,

Antônio³

et al. 2016

Endocrine-Related Cancer

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Deregulation of the IGF system observed in human tumors indicates a role in malignant cell transformation and in tumor cell proliferation. Although overexpression of the IGF2 and IGF1R genes was described in adrenocortical tumors (ACTs), few studies reported their profiles in pediatric ACTs. In this study, the IGF2 and IGF1R expression was evaluated by RT-qPCR according to the patient's clinical/pathological features in 60 pediatric ACT samples, and IGF1R protein was investigated in 45 samples by immunohistochemistry (IHC). Whole transcriptome and functional assays were conducted after IGF1R inhibition with OSI-906 in NCI-H295A cell line. Significant IGF2 overexpression was found in tumor samples when compared with non-neoplastic samples (P < 0.001), significantly higher levels of IGF1R in patients with relapse/metastasis (P = 0.031) and moderate/strong IGF1R immunostaining in 62.2% of ACTs, but no other relationship with patient survival and clinical/pathological features was observed. OSI-906 treatment downregulated genes associated with MAPK activity, induced limited reduction of cell viability and increased the apoptosis rate. After 24 h, the treatment also decreased the expression of genes related to the steroid biosynthetic process, the protein levels of the steroidogenic acute regulatory protein (STAR), and androgen secretion in cell medium, supporting the role of IGF1R in steroidogenesis of adrenocortical carcinoma cells. Our data showed that the IGF1R overexpression could be indicative of aggressive ACTs in children. However, in vitro treatments with high concentrations of OSI-906 (>1 μM) showed limited reduction of cell viability, suggesting that OSI-906 alone could not be a suitable therapy to abolish carcinoma cell growth. 23:6Research R C P Lira et al.IGF1R in pediatric adrenocortical tumor IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis

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“…The pathogenic p.S45P mutation of CTNNB1 gene, which results in abnormal beta-catenin nuclear accumulation [20,21], is characteristic of NCI-H295R cells. The effect of AA on beta-catenin sub-cellular localization was investigated.…”

Section: Aa Affects Beta-catenin Translocation Into the Nucleus In Ncmentioning

confidence: 99%

Antisecretive and Antitumor Activity of Abiraterone Acetate in Human Adrenocortical Cancer: A Preclinical Study

Fiorentini¹,

Fragni²,

Perego³

et al. 2016

The Journal of Clinical Endocrinology & Metabolism

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Context: Patients with adrenocortical carcinoma (ACC) frequently suffer from cortisol excess, which portends a negative prognosis. Rapid control of cortisol hypersecretion and tumor growth are the main goals of ACC therapy. Abiraterone acetate (AA) is a potent inhibitor of 17alpha-hydroxylase/17,20-lyase, a key enzyme of adrenal steroidogenesis.Objective: To investigate the therapeutic use of AA in preclinical models of ACC.Design: AA antisecretive and antiproliferative effects were investigated in vitro using NCI-H295R and SW13 ACC cell lines and human primary ACC cell cultures, as well as in vivo using immunodeficient mice.Methods: Steroid secretion, cell viability and proliferation were analyzed in untreated and AA-treated ACC cells. The ability of AA to affect the Wnt/beta-catenin pathway in NCI-H295R cells was also analyzed.Progesterone receptor (PgR) gene was silenced by the RNA interference approach. The antitumor efficacy of AA was confirmed in vivo in NCI-H295R cells xenografted in immunodeficient mice.Results: AA reduced the secretion of both cortisol and androgens, increased production of progesterone and induced a concentration-dependent decrease of cell viability in the NCI-H295R cells and primary secreting ACC cultures. AA also reduced beta-catenin nuclear accumulation in NCI-H295R cells. AA administration to NCI-H295R-bearing mice enhanced progesterone levels and inhibited tumor growth. The cytotoxic effect of AA was prevented by either blocking PgR or by gene silencing.Conclusion: AA is able to inhibit hormone secretion and growth of ACC both in vitro and in vivo. It also reduces beta-catenin nuclear accumulation. The cytotoxic effect of AA appears to require PgR.

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

Cited by 64 publications

References 46 publications

Unraveling the expression of the oncogene YAP1, a Wnt/beta-catenin target, in adrenocortical tumors and its association with poor outcome in pediatric patients

Unraveling the expression of the oncogene YAP1, a Wnt/beta-catenin target, in adrenocortical tumors and its association with poor outcome in pediatric patients

IGF2 and IGF1R in pediatric adrenocortical tumors: roles in metastasis and steroidogenesis

Antisecretive and Antitumor Activity of Abiraterone Acetate in Human Adrenocortical Cancer: A Preclinical Study

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