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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.

SUBMITTER: Chen X

PROVIDER: S-EPMC7739006 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Chen Xun X Zhang Qian Q Dang Xiaoqian X Song Tao T Wang Yufei Y Yu Zirui Z Zhang Shihui S Fan Jinzhu J Cong Fei F Zhang Wentao W Duan Ning N

Journal of Cancer 20210101 2

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 ...[more]

PMID: 33391445

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Project description:Osteosarcoma is the most common type of pediatric bone tumor. Despite great advances in chemotherapy during the past decades, the survival rates of osteosarcoma patients remain unsatisfactory. Drug resistance is one of the main reasons, leading to treatment failure and poor prognosis. Previous reports correlated expression of cluster of differentiation 44 (CD44) with drug resistance and poor survival of osteosarcoma patients, however the underlying mechanisms are poorly defined. Here, we investigated the role of CD44 in the regulation of drug chemoresistance, using osteosarcoma cells isolated from mice carrying a mutation of the tumor suppressor neurofibromatosis type 2 (Nf2) gene. CD44 expression was knocked-down in the cells using CRISPR/Cas9 approach. Subsequently, CD44 isoforms and mutants were re-introduced to investigate CD44-dependent processes. Sensitivity to doxorubicin was analyzed in the osteosarcoma cells with modified CD44 expression by immunoblot, colony formation- and WST-1 assay. To dissect the molecular alterations induced by deletion of Cd44, RNA sequencing was performed on Cd44-positive and Cd44-negative primary osteosarcoma tissues isolated from Nf2-mutant mice. Subsequently, expression of candidate genes was evaluated by quantitative reverse transcription PCR (qRT-PCR). Our results indicate that CD44 increases the resistance of osteosarcoma cells to doxorubicin by up-regulating the levels of multidrug resistance (MDR) 1 protein expression, and suggest the role of proteolytically released CD44 intracellular domain, and hyaluronan interactions in this process. Moreover, high throughput sequencing analysis identified differential regulation of several apoptosis-related genes in Cd44-positive and -negative primary osteosarcomas, including p53 apoptosis effector related to PMP-22 (Perp). Deletion of Cd44 in osteosarcoma cells led to doxorubicin-dependent p53 activation and a profound increase in Perp mRNA expression. Overall, our results suggest that CD44 might be an important regulator of drug resistance and suggest that targeting CD44 can sensitize osteosarcoma to standard chemotherapy.

Dataset Information

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

Publications

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

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