title: CD40 stimulation induces vincristine resistance via AKT activation and MRP1 expression in a human multiple myeloma cell line.
abstract: 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.
authors.affiliation: Advanced Research Center for Multiple Myeloma, College of Medicine, Inje University, Busan, Republic of Korea. swlee@inje.ac.kr
authors.forename: Soo-Woong
authors.initials: SW
authors.lastname: Lee
authors.forename: Hae-Yun
authors.initials: HY
authors.lastname: Cho
authors.forename: Giyoun
authors.initials: G
authors.lastname: Na
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Yoo
authors.forename: Su-Kil
authors.initials: SK
authors.lastname: Seo
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Hur
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Chae Kwan
authors.initials: CK
authors.lastname: Lee
authors.forename: Inhak
authors.initials: I
authors.lastname: Choi
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005786:Gene Expression Regulation; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014750:Vincristine / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019013:CD40 Antigens; D023201:CD40 Ligand; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051057:Proto-Oncogene Proteins c-akt; D014750:Vincristine; C421109:multidrug resistance-associated protein 1