Loss of β-catenin in adrenocortical cancer cells causes growth inhibition and reversal of epithelial-to-mesenchymal transition

Salomón, A.; Kéramidas, Michelle; Maisin, Cécile; Thomas, Michaël

doi:10.18632/oncotarget.3222

Cited by 32 publications

(18 citation statements)

References 50 publications

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“…Our findings support those of Salomon et al [39], where siRNAs were used to silence beta-catenin expression in H295R. They found that silencing beta-catenin decreased cell growth, decreased migration and invasion, increased cell apoptosis, and induced cell cycle S/G2 arrest.…”

Section: Discussionsupporting

confidence: 92%

microRNA-431 as a Chemosensitizer and Potentiator of Drug Activity in Adrenocortical Carcinoma

et al. 2019

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Background Adrenocortical carcinoma (ACC) is a rare endocrine cancer with treatments limited in efficacy for metastatic disease. New molecular targeted therapies have yet to improve patient outcomes. In contrast, established treatment regimens of adrenolytics and chemotherapy have demonstrated treatment benefit, although admittedly in a minority of patients. Identification of microRNAs (miRNAs) in patients responsive to adjuvant therapy may offer a means to sensitize patients with progressive disease to existing adjuvant regimens. Materials and Methods Samples from primary ACC tumors of 10 Stage IV patients were examined for differentially expressed miRNAs between a “sensitive” and “resistant” cohort. Candidate microRNAs were restored via transfection in two functional ACC cell lines. Gain of function and effects on apoptosis and cell cycle were assessed. Results microRNA‐431 (miR‐431) was underexpressed in patients with ACC with progressive disease undergoing adjuvant therapy. Restoration of miR‐431 in vitro decreased the half maximal inhibitory concentrations of doxorubicin and mitotane, with markedly increased apoptosis. We found that a reversal of epithelial‐mesenchymal transition underlies the action of miR‐431 with doxorubicin treatment, with Zinc Finger E‐Box Binding Homeobox 1 implicated as the molecular target of miR‐431 in ACC. Conclusion This is the first report of the potential of miRNA therapy to sensitize ACC to current established adjuvant therapy regimens, which may mitigate the resistance underlying treatment failure in patients with advanced ACC. Effective and well‐studied methods of targeted miRNA delivery in existence hints at the imminent translatability of these findings. Implications for Practice Adrenocortical carcinoma (ACC) is a rare endocrine cancer with outcomes not improving despite extensive research and new targeted therapies. Mitotane and etoposide/doxorubicin/cisplatin chemotherapy is trial validated for improved recurrence‐free survival. However, a minority of patients experience sustained benefit. Significant side effects exist for this regimen, with patients often unable to attain target drug doses shown to give survival benefit. This preclinical study examines the role of microRNAs in sensitizing ACC to doxorubicin or mitotane. This study offers an important bridge between new and existing cancer treatments, offering an imminently translatable approach to the treatment of adrenocortical carcinoma.

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Section: Discussionsupporting

confidence: 92%

microRNA-431 as a Chemosensitizer and Potentiator of Drug Activity in Adrenocortical Carcinoma

et al. 2019

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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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“…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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Loss of β-catenin in adrenocortical cancer cells causes growth inhibition and reversal of epithelial-to-mesenchymal transition

Cited by 32 publications

References 50 publications

microRNA-431 as a Chemosensitizer and Potentiator of Drug Activity in Adrenocortical Carcinoma

microRNA-431 as a Chemosensitizer and Potentiator of Drug Activity in 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

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