Document Detail

CD40 stimulation induces vincristine resistance via AKT activation and MRP1 expression in a human multiple myeloma cell line.
MedLine Citation:
PMID:  22445357     Owner:  NLM     Status:  MEDLINE    
Various co-stimulatory receptors are expressed in multiple myeloma (MM) both in immune microenvironment and in the tumor microenvironment in vivo. In relapsed human MM, these receptors are known to increase cell proliferation and induce conventional drug resistance. However, the mechanism of drug resistance induced via co-stimulatory receptors is poorly understood. In this study, we examined the role of CD40 expressed on MM cell lines. Out of all of the KMS MM cell lines, the KMS28BM cells expressed high levels of the CD40 receptor. When stimulated with anti-CD40 antibody or recombinant human CD40L, the proliferation of KMS28BM cells was increased 1.7 fold. In CD40-stimulated KMS28BM cells, signaling via the AKT pathway caused an increase in the expression of multidrug resistance-associated gene 1 (MRP1) and IL-6 by 2.2 fold and 30 fold, respectively, but not the MDR1 gene. Furthermore, CD40-stimulated KMS28BM cells were observed to be substantially resistant to the anticancer drug vincristine, and when cells were treated with the MRP1 specific inhibitor, MK-571, drug resistance was decreased. We also found that CD40-stimulated, MRP1-expressing KMS28BM cells significantly increased calcein efflux, and calcein efflux was inhibited through treatment with MK-571. Therefore, blocking CD40 and inhibiting MRP1 are potential targets to treat CD40-induced drug resistance in multiple myeloma.
Soo-Woong Lee; Hae-Yun Cho; Giyoun Na; Mi Ra Yoo; Su-Kil Seo; Dae Young Hur; Jin Han; Chae Kwan Lee; Inhak Choi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-03-14
Journal Detail:
Title:  Immunology letters     Volume:  144     ISSN:  1879-0542     ISO Abbreviation:  Immunol. Lett.     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-04-30     Completed Date:  2012-08-27     Revised Date:  2012-10-17    
Medline Journal Info:
Nlm Unique ID:  7910006     Medline TA:  Immunol Lett     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  41-8     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier B.V. All rights reserved.
Advanced Research Center for Multiple Myeloma, College of Medicine, Inje University, Busan, Republic of Korea.
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MeSH Terms
Antigens, CD40 / metabolism*
Antineoplastic Agents, Phytogenic / pharmacology*
CD40 Ligand
Cell Line, Tumor
Drug Resistance, Neoplasm*
Gene Expression Regulation
Multidrug Resistance-Associated Proteins / genetics,  metabolism*
Multiple Myeloma / metabolism
Proto-Oncogene Proteins c-akt / genetics,  metabolism*
Signal Transduction
Vincristine / pharmacology*
Reg. No./Substance:
0/Antigens, CD40; 0/Antineoplastic Agents, Phytogenic; 0/Multidrug Resistance-Associated Proteins; 0/multidrug resistance-associated protein 1; 147205-72-9/CD40 Ligand; 57-22-7/Vincristine; EC Proteins c-akt
Comment In:
Immunol Lett. 2012 Sep;147(1-2):85-6   [PMID:  22819355 ]

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