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

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 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.

CTBP1 strengthens the cisplatin resistance of gastric cancer cells by upregulating RAD51 expression

“…RAD51 is a protein observed in different types of cells, such as those of ovarian, colorectal and breast cancer, and its expression is key in the process of homologous recombination, which is one of the major mechanisms of the DNA damage response ( 29 ). When DNA damage occurs, RAD51 forms nucleofilaments with other repair proteins, such as BRCA2 and partner and localizer of BRCA2, on single-stranded DNA to facilitate homologous strand pairing and strand exchange during the DNA damage repair process ( 30 , 31 ). RAD51 has been reported to enhance the occurrence and development of colon cancer ( 32 ).…”

“…As a transcription factor, CTBP1 serves a crucial role in regulating cell proliferation and apoptosis in different types of cells, such as breast cancer, osteosarcoma and ovarian cancer (14,(30)(31)(32). Furthermore, CTBP1 enhances the occurrence and development of different types of cancer (26).…”

The interaction between PDCD4 and YB1 is critical for cervical cancer stemness and cisplatin resistance

“…Published data have shown that acquirement of cancer stemness was associated with MDR and its related adverse prognosis. 6,[16][17][18] As a typical protein for MDR, the expression of multidrug transporter P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter protein encoded by the MDR1 has been identified as a crucial regulator for clinical MDR and stemness in cervical cancer. 5,6 Similar to the inhibitory role of PDCD4 in cancer cell growth, proliferation, migration, invasion, and carcinogenesis, [19][20][21][22][23] we specifically found that the reduced PDCD4 induced the acquirement of cancer stemness, resulting in the increased cisplatin resistance on cervical cancer, which was related to the increase in MDR1 expression of cervical cancer cells.…”

Biological evidence of cancer stem-like cells and recurrent disease in osteosarcoma

“…Oct4 knockdown with siRNA induced a significant decrease in cell proliferation, invasion, and apoptosis [76] . TBL1XR1 is a transcriptional co-factor which is overexpressed in osteosarcoma patients [77] . Its overexpression in MG63 and U2-OS cell lines induced a CSC phenotype in contrast to its repression.…”

“…Its overexpression in MG63 and U2-OS cell lines induced a CSC phenotype in contrast to its repression. TBL1XR1 thus provides osteosarcoma cells with tumorigenic properties and promotes the recurrence of osteosarcoma in a STAT-3 signaling dependent manner [77] . Transcriptional complexes can also modulate osteosarcoma drug resistance.…”