Abstract
Ciclesonide is an FDA-approved glucocorticoid used to treat asthma and allergic rhinitis. However, whether it has anticancer and anti-cancer stem cell (CSC) effects is unknown. This study focused on investigating the effect of ciclesonide on breast cancer and CSCs and determining its underlying mechanism. Here, we showed that ciclesonide inhibits breast cancer and CSC formation. Similar glucocorticoids—dexamethasone and prednisone—did not inhibit CSC formation. Ciclesonide-induced glucocorticoid receptor (GR) degradation was dependent on ubiquitination. We showed via GR small interfering RNA (siRNA) that GR plays an important role in CSC formation. We showed via western blot and immunofluorescence assays that ciclesonide reduces the nuclear level of GR. The GR antagonist RU-486 also inhibited CSC formation. Ciclesonide reduced the protein level of the Hippo transducer Yes-associated protein (YAP). GR siRNA induced a decrease in YAP protein expression and inhibited mammosphere formation. The YAP inhibitor verteporfin inhibited CSC formation and transcription of the connective tissue growth factor and cysteine-rich protein 61 genes. The GR/YAP1 pathway regulated breast CSC formation. We showed that the GR/YAP signaling pathway regulates breast CSC formation and revealed a new approach for targeting GR and YAP to inhibit CSC formation.
Highlights
The Hippo pathway, discovered in the fruit fly Drosophila melanogaster, is a tumor suppressor signaling pathway that controls cell growth, tissue homeostasis, and organ size through the regulation of cell proliferation and apoptosis [1]
We showed via glucocorticoid receptor (GR) small interfering RNA that GR plays an important role in cancer stem cell (CSC) formation
We showed via GR small interfering RNA (siRNA) that ciclesonide-induced ubiquitin-dependent GR degradation and GR
Summary
The Hippo pathway, discovered in the fruit fly Drosophila melanogaster, is a tumor suppressor signaling pathway that controls cell growth, tissue homeostasis, and organ size through the regulation of cell proliferation and apoptosis [1]. The LATS1/2 kinase phosphorylates and inhibits the Hippo pathway effectors Yes-associated protein (YAP) and Tafazzin (TAZ). Activation of YAP/TAZ has been found in human cancers, including metastatic breast cancer, and increases the self-renewal of cancer stem cells (CSCs) [4,5,6]. Aberrant activation of YAP/TAZ induces CSC traits, anoikis resistance, epithelial-mesenchymal transition (EMT), drug resistance, and metastasis [2]. The activation of GR is fundamental for CSCs self-renewal and chemoresistance of breast cancer cells, and GR signaling affects the mechanical properties of the tumor microenvironment, promoting YAP nuclear accumulation and activation [1]. An increase in stress hormones during breast cancer progression results in GR activation at distant metastatic sites and reduces survival [10]. GR activation induces heterogeneity and metastasis, and GCs promote breast cancer metastasis. Radiation-induced GR expression increases the CSC population in prostate cancer through SGK1-Wnt/β-catenin signaling, limiting the efficacy of radiotherapy for prostate cancer treatment [11]
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