Silencing Mutated β-Catenin Inhibits Cell Proliferation and Stimulates Apoptosis in the Adrenocortical Cancer Cell Line H295R

Gaujoux, Sébastien; Hantel, Constanze; Launay, Pierre; Bonnet, Stéphane; Perlemoine, Karine; Lefèvre, Lise; Guillaud‐Bataille, Marine; Beuschlein, Felix; Tissier, Frédérique; Bertherat, Jérôme; Rizk-Rabin, Marthe; Ragazzon, Bruno

doi:10.1371/journal.pone.0055743

Cited by 48 publications

(47 citation statements)

References 20 publications

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“…Mutations in β-catenin have been associated with poor prognosis in patients with ACC, and higher-grade ACC is associated with higher β-catenin expression (25). Silencing of β-catenin in NCI-H295R has been shown to decrease proliferation, induce cell cycle arrest and apoptosis, reverse the EMT phenotype, and inhibit in vivo tumor development (26, 27). These findings suggest that the WNT/β-catenin pathway plays a major role in ACC tumorigenesis and may be an effective therapeutic target for ACC treatment.…”

Section: Discussionmentioning

confidence: 99%

Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma

Satoh

Zhang

et al. 2016

Clinical Cancer Research

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Purpose Adrenocortical carcinoma (ACC) is a rare and aggressive cancer, and no current effective therapy is available for locally advanced and metastatic ACC. Drug repurposing is an emerging approach for identifying new indications for existing drugs, especially for rare cancers such as ACC. The objective of this study was to use quantitative high-throughput screening to identify agents with antineoplastic activity against ACC. Experimental Design A screening of 4,292 compounds was performed on three ACC cell lines: BD140A, SW-13, and NCI-H295R. Results Twenty-one active compounds were identified, with an efficacy of >80% in all three cell lines. Of these, niclosamide showed higher efficacy and lower IC50 than established anti-ACC drugs. We then validated niclosamide-inhibited cellular proliferation in all three ACC cell lines. Next, we investigated the mechanism by which niclosamide inhibited ACC cell proliferation, and found that it induced caspase-dependent apoptosis and G1 cell cycle arrest. Niclosamide also decreased cellular migration and reduced the level of mediators of epithelial-to-mesenchymal transition, such as N-cadherin and vimentin. Furthermore, niclosamide treatment resulted in decreased expression of β-catenin. We also evaluated the effect of niclosamide on energy metabolism in ACC cell lines and found it resulted in mitochondrial uncoupling. Niclosamide treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Conclusions Our findings suggest that niclosamide has anti-ACC activity through its inhibition of multiple altered cellular pathways and cellular metabolism in ACC. Our results provide a preclinical rationale for evaluating niclosamide therapy in a clinical trial for ACC.

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Section: Discussionmentioning

confidence: 99%

Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma

Satoh

Zhang

et al. 2016

Clinical Cancer Research

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“…H295R human ACC cells harbor an activating β-catenin mutation. Knockdown of β-catenin in these cells causes cell cycle arrest and increased cell death in vitro , and complete tumor regression in vivo (Gaujoux et al, 2013; Salomon et al, 2015). Small molecule antagonism of the TCF/β-catenin complex also results in H295R growth inhibition (Doghman et al, 2008).…”

Section: Wnt/β-catenin Signalingmentioning

confidence: 99%

Cell signaling pathways in the adrenal cortex: Links to stem/progenitor biology and neoplasia

Penny

Finco

Hammer

2017

Molecular and Cellular Endocrinology

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The adrenal cortex is a dynamic tissue responsible for the synthesis of steroid hormones, including mineralocorticoids, glucocorticoids, and androgens in humans. Advances have been made in understanding the role of adrenocortical stem/progenitor cell populations in cortex homeostasis and self-renewal. Recently, large molecular profiling studies of adrenocortical carcinoma (ACC) have given insights into proteins and signaling pathways involved in normal tissue homeostasis that become dysregulated in cancer. These data provide an impetus to examine the cellular pathways implicated in adrenocortical disease and study connections, or lack thereof, between adrenal homeostasis and tumorigenesis, with a particular focus on stem and progenitor cell pathways. In this review, we discuss evidence for stem/progenitor cells in the adrenal cortex, proteins and signaling pathways that may regulate these cells, and the role these proteins play in pathologic and neoplastic conditions. In turn, we also examine common perturbations in adrenocortical tumors (ACT) and how these proteins and pathways may be involved in adrenal homeostasis.

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“…The first results of effectiveness of targeting the Wnt signaling pathway in ACC comes from in vitro inhibition of ACC cell proliferation by the small-molecule inhibitor PKF115-584 (Doghman et al 2008). Gaujoux et al showed that b-catenin silencing caused decreased cell proliferation, alterations in the cell cycle and increased apoptosis in adrenocortical cancer cells in vitro (Gaujoux et al 2013). Clinical trials with Wnt inhibitors in ACC have not yet been performed.…”

Section: Future Directions and Pathway Driven Therapiesmentioning

confidence: 99%

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

Creemers¹,

Hofland²,

Korpershoek³

et al. 2015

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis. Discrimination between ACCs and adrenocortical adenomas (ACAs) remains challenging, with the current gold standard being the Weiss score, consisting of several histopathological characteristics. However, new markers like Ki67, a marker for proliferation, and the staining of reticulins are promising not only as it comes to identifying malignancy but also as prognostic markers in patients with ACC. Currently, surgery is still the only curative treatment for ACC. Mitotane, an adrenolytic drug, is used in the adjuvant setting and in case of metastatic or advanced disease. Patients with progressive disease are frequently treated with mitotane, alone or in combination with etoposide, doxorubicine and cisplatin. Radiotherapy is indicated in selected cases. The low response rates and high toxicity of the systemic therapies emphasize the need for markers that enable the identification of responders and non-responders. Consequently, research is focusing on predictive factors varying from the expression of DNA repair genes to clinical patient characteristics. Subgroups of ACC with different prognosis have been identified based on transcriptome characteristics. As a conclusion from large molecular studies, ACCs appear to harbor many abnormalities compared to ACAs. Altered pathways driving ACC pathogenesis include the IGF, TP53 and the Wnt signaling pathway, allowing these as new potential targets for medical therapy. However, despite efforts in preclinical and clinical studies investigating efficacy of targeting these pathways, most novel therapies appear to be effective in only a subset of patients with ACC. New treatment concepts are therefore urgently needed.

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Silencing Mutated β-Catenin Inhibits Cell Proliferation and Stimulates Apoptosis in the Adrenocortical Cancer Cell Line H295R

Cited by 48 publications

References 20 publications

Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma

Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma

Cell signaling pathways in the adrenal cortex: Links to stem/progenitor biology and neoplasia

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

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