Targeting the CtBP1-FOXM1 transcriptional complex with small molecules to overcome MDR1-mediated chemoresistance in osteosarcoma cancer stem cells

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Chemoresistance is a major barrier for the chemotherapy of osteosarcoma.The induction of multidrug resistance protein 1 (MDR1), an ATP-dependent transporter, can efflux anti-cancer drugs, thereby decreasing chemosensitivity.However, an actual involvement of MDR1 in the chemoresistance of osteosarcoma cells has not been established.We obtained two cisplatin (CDDP)-resistant osteosarcoma cancer stem cell (CSC) lines using sphere formation medium supplemented with CDDP.These two CDDP-resistant CSC cell lines showed substantial cell proliferation, colony formation, cell invasion, and in vivo tumor growth in the presence of CDDP.Microarray analysis revealed that three genes, MDR1, FOXM1 (forkhead box M1), and CtBP1 (C-Terminal binding protein 1), showed significant overexpression in both cell lines.Mechanistically, CtBP1 assembled with FOXM1 to form a transcriptional complex, which docked onto the MDR1 promoter to activate MDR1 expression.Knockdown or inhibition of the CtBP1-FOXM1 components with specific small molecules, including NSM00158 and NSC95397 for CtBP1 and RCM1 for FOXM1, significantly repressed MDR1 expression.Administration of these three small molecules also significantly inhibited tumor growth in mouse tumor xenograft model.The MDR1-mediated chemoresistance could be reversed by NSM00158 and RCM1.Collectively, our data revealed that the CtBP1-FOXM1 complex activated MDR1 expression and that targeting this complex with their specific inhibitors could reverse MDR1-mediated chemoresistance both in vitro and in vivo.Our results indicate a new therapeutic strategy for overcoming chemoresistance during osteosarcoma treatment.

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