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

AI Article Synopsis

  • Chemoresistance is a significant challenge in osteosarcoma treatment, primarily due to the induction of multidrug resistance protein 1 (MDR1), which can efflux anti-cancer drugs and reduce their effectiveness.
  • Researchers created two cisplatin-resistant osteosarcoma cancer stem cell lines, which exhibited increased cell growth and tumor formation even in the presence of the chemotherapy drug.
  • The study identified a transcriptional complex involving CtBP1 and FOXM1 that promotes MDR1 expression, and using specific inhibitors against these proteins successfully reduced tumor growth and reversed chemoresistance, suggesting a potential new treatment strategy for osteosarcoma.

Article Abstract

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 tumor growth in the presence of CDDP. Microarray analysis revealed that three genes, , (forkhead box M1), and (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 promoter to activate 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 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 expression and that targeting this complex with their specific inhibitors could reverse MDR1-mediated chemoresistance both and . Our results indicate a new therapeutic strategy for overcoming chemoresistance during osteosarcoma treatment.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739006PMC
http://dx.doi.org/10.7150/jca.50255DOI Listing

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