Niclosamide induces miR-148a to inhibit PXR and sensitize colon cancer stem cells to chemotherapy
| Autor: | Lucile Bansard, Océane Bouvet, Elisa Moutin, Gaétan Le Gall, Alessandro Giammona, Elodie Pothin, Marion Bacou, Cédric Hassen-Khodja, Benoit Bordignon, Jean François Bourgaux, Michel Prudhomme, Frédéric Hollande, Julie Pannequin, Jean Marc Pascussi, Chris Planque |
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| Přispěvatelé: | Guerineau, Nathalie C., Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), BioCampus (BCM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), University of Melbourne |
| Rok vydání: | 2022 |
| Předmět: |
cancer stem cell
PXR [SDV]Life Sciences [q-bio] colorectal cancer [SDV.CAN]Life Sciences [q-bio]/Cancer [SDV.BC]Life Sciences [q-bio]/Cellular Biology digestive system Biochemistry Mice [SDV.CAN] Life Sciences [q-bio]/Cancer Cell Line Tumor Genetics Animals Humans [SDV.BC] Life Sciences [q-bio]/Cellular Biology Pregnane X Receptor Cell Biology tumor recurrence digestive system diseases high-content screen Gene Expression Regulation Neoplastic [SDV] Life Sciences [q-bio] MicroRNAs miR-148a Colonic Neoplasms Neoplastic Stem Cells Niclosamide Neoplasm Recurrence Local Developmental Biology |
| Zdroj: | Stem Cell Reports Stem Cell Reports, 2022, 17 (4), pp.835-848. ⟨10.1016/j.stemcr.2022.02.005⟩ |
| ISSN: | 2213-6711 |
| DOI: | 10.1016/j.stemcr.2022.02.005 |
| Popis: | International audience; Tumor recurrence is often attributed to cancer stem cells (CSCs). We previously demonstrated that down-regulation of Pregnane X Receptor (PXR) decreases the chemoresistance of CSCs and prevents colorectal cancer recurrence. Currently, no PXR inhibitor is usable in clinic. Here, we identify miR-148a as a targetable element upstream of PXR signaling in CSCs, which when over-expressed decreases PXR expression and impairs tumor relapse after chemotherapy in mouse tumor xenografts. We then develop a fluorescent reporter screen for miR-148a activators and identify the anti-helminthic drug niclosamide as an inducer of miR-148a expression. Consequently, niclosamide decreased PXR expression and CSC numbers in colorectal cancer patient-derived cell lines and synergized with chemotherapeutic agents to prevent CSC chemoresistance and tumor recurrence in vivo. Our study suggests that endogenous miRNA inducers is a viable strategy to down-regulate PXR and illuminates niclosamide as a neoadjuvant repurposing strategy to prevent tumor relapse in colon cancer. |
| Databáze: | OpenAIRE |
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