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Dysregulated MDR1 by PRDM1/Blimp1 Is Involved in the Doxorubicin Resistance of Non-Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma
- Source :
- Chemotherapy. 67:12-23
- Publication Year :
- 2021
- Publisher :
- S. Karger AG, 2021.
-
Abstract
- Introduction: The chemoresistance mechanism of diffuse large B-cell lymphoma (DLBCL) is still poorly understood, and patient prognosis remains unsatisfactory. This study aimed to investigate drug resistance mechanisms in non-germinal center B-cell-like (non-GCB) DLBCL. Methods: Doxorubicin (DOX)-resistant OCI-Ly3 cells were generated through long-term incubation of cells in a medium with gradually increasing DOX concentrations. The expression levels of genes related to drug metabolism were determined using a functional gene grouping polymerase chain reaction (PCR) array. Drug-resistant proteins were identified using bioinformatics, and molecular association networks were subsequently generated. The association and mechanism of key genes were determined using a dual-luciferase reporter assay System and chromatin immunoprecipitation (ChIP). The expression of drug-resistant genes and target genes was then measured using Western blotting and immunohistochemistry. The correlation between gene expressions was analyzed using Spearman’s rank correlation coefficient. Results: Using the PCR array, MDR1 was identified as the key gene that regulates DOX resistance in OCI-Ly3/DOX-A100, a non-GCB DLBCL cell line. The dual-luciferase reporter assay system demonstrated that MDR1 transcription could be inhibited by PRDM1. ChIP results showed that PRDM1 had the ability to bind to the promoter region (−1,132 to −996) of MDR1. In OCI-Ly3/DOX cells, NF-κB activity and PRDM1 expression decreased with an increase in drug-resistant index, whereas MDR1 expression increased with enhanced drug resistance. Immunohistochemical analysis revealed that relative MDR1 expression was higher than that of PRDM1 in human DLBCL tissue samples. A negative correlation was observed between MDR1 and PRDM1. Conclusion: In non-GCB DLBCL cells, NF-κB downregulates PRDM1 and thereby promotes MDR1 transcription by terminating PRDM1-induced transcriptional inhibition of MDR1. Such a mechanism may explain the reason for disease recurrence in non-GCB DLBCL after R-CHOP or combined CHOP with bortezomib treatment. Our findings may provide a potential therapeutic strategy for reducing drug resistance in patients with DLBCL.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B
Drug resistance
CHOP
hemic and lymphatic diseases
Antineoplastic Combined Chemotherapy Protocols
Drug Discovery
PRDM1
Humans
Pharmacology (medical)
Pharmacology
Reporter gene
Chemistry
Promoter
General Medicine
Prognosis
Infectious Diseases
Gene Expression Regulation
Oncology
Doxorubicin
Drug Resistance, Neoplasm
Cell culture
Cancer research
Lymphoma, Large B-Cell, Diffuse
Positive Regulatory Domain I-Binding Factor 1
Neoplasm Recurrence, Local
Germinal center B-cell like diffuse large B-cell lymphoma
Rituximab
Chromatin immunoprecipitation
Subjects
Details
- ISSN :
- 14219794 and 00093157
- Volume :
- 67
- Database :
- OpenAIRE
- Journal :
- Chemotherapy
- Accession number :
- edsair.doi.dedup.....fc01fe2517625c429996ca7d103f0ac1
- Full Text :
- https://doi.org/10.1159/000520070