Niclosamide induces miR-148a to inhibit PXR and sensitize colon cancer stem cells to chemotherapy

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Bansard, Lucile | Bouvet, Océane | Moutin, Elisa | Le Gall, Gaétan | Giammona, Alessandro | Pothin, Elodie | Bacou, Marion | Hassen-Khodja, Cédric | Bordignon, Benoit | Bourgaux, Jean François | Prudhomme, Michel | Hollande, Frédéric | Pannequin, Julie | Pascussi, Jean-Marc | Planque, Chris

Edité par CCSD ; Elsevier -

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.

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