ABCG2 expression, function, and promoter methylation in human multiple myeloma

Abstract

We investigated the role of the breast cancer resistance protein (BCRP/ABCG2) in drug resistance in multiple myeloma (MM). Human MM cell lines, and MM patient plasma cells isolated from bone marrow, were evaluated for ABCG2 mRNA expression by quantitative polymerase chain reaction (PCR) and ABCG2 protein, by Western blot analysis, immunofluorescence microscopy, and flow cytometry. ABCG2 function was determined by measuring topotecan and doxorubicin efflux using flow cytometry, in the presence and absence of the specific ABCG2 inhibitor, tryprostatin A. The methylation of the ABCG2 promoter was determined using bisulfite sequencing. We found that ABCG2 expression in myeloma cell lines increased after exposure to topotecan and doxorubicin, and was greater in logphase cells when compared with quiescent cells. Myeloma patients treated with topotecan had an increase in ABCG2 mRNA and protein expression after treatment with topotecan, and at relapse.

Involvement of breast cancer resistance protein expression on rheumatoid arthritis synovial tissue macrophages in resistance to methotrexate and leflunomide

“…There may be epigenetic reasons for this, since aberrant promoter methylation inactivates the BCRP gene (31,32) or alternatively, some alterations in environmental conditions may up-regulate BCRP expression as observed under hypoxic conditions (30) or after folate supplementation to sustain folate homeostasis (33). One pathophysiologic condition in RA synovial tissue that could be implicated in BCRP expression is its hypoxic environment.…”

Identification of genes that confer tumor cell resistance to the Aurora B kinase inhibitor, AZD1152

“…33 Interestingly, both BCRP expression and resistance to JNJ-7706621 were fully reversed following drug withdrawal, 33 indicating that BRCP-mediated resistance does not require a genomic alteration. Activation of nuclear hormone receptors 34 and promoter methylation 35 have been demonstrated to control the transcription of BCRP. Yet another layer of regulatory complexity derives from studies of doxorubicin-resistance wherein the substrate specificity of murine BCRP has been shown to be altered by point mutation.…”

Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors

“…SP cells from RPMI 8226 exhibited fine nuclear chromatin and expressed high levels of ABCG2, one of the ABC transporters associated with drug resistance (Figures 2a and b). [7][8][9] Neither SP cells nor MP cells expressed ABCB1 and ABCC1 (Figure 2b). Notably, SP fraction contained CD138 high cells and subpopulation with CD138 low , but most MP cells were CD138 high phenotype.…”

“…Side population (SP) cells are identified by their ability to efflux Hoechst 33342 dye, and these cells have been shown to highly express ABCG2 transporter that is responsible for drug resistance. [6][7][8][9] In MM, the distinct fraction of SP cells has been detected in both MM cell lines and primary MM cells. 10 Matsui et al 11 have found the clonogenic property and drug resistance in SP fraction of MM cells, and reported the relationship between SP fraction and CD138 À phenotype.…”