Potential crosstalk of the interleukin-6-heme oxygenase-1-dependent mechanism involved in resistance to lenalidomide in multiple myeloma cells.
FEBS J
; 283(5): 834-49, 2016 Mar.
Article
em En
| MEDLINE
| ID: mdl-26700310
ABSTRACT
Interleukin (IL)-6 is one of the most important survival factors in multiple myeloma (MM), and determines the poor prognosis of MM. IL-6 mainly has a paracrine bone marrow stromal cell origin and an autocrine MM cell origin. As an enzyme having cytoprotective effects, heme oxygenase-1 (HO-1) promotes the growth and drug resistance of various malignant tumors. HO-1 expression levels in bone marrow CD138(+) cells of MM patients were significantly higher than those in healthy donors, and positively correlated with both serum IL-6 and intracellular IL-6 mRNA expression levels. Culture of U266, RPMI8226 and CD138(+) cells with exogenous IL-6 in vitro induced high HO-1 expression levels and allowed them to resist lenalidomide. It is hypothesized that this was probably attributable to IL-6-mediated activation of the Janus kinase 2-signal transducer and activator of transcription 3 pathway. In contrast, without IL-6 coculture, enhanced HO-1 expression in U266, RPMI8226 and bone marrow CD138(+) cells from MM patients significantly inreased IL-6 mRNA expression levels and facilitated autocrine IL-6 production. The findings were associated with high HO-1 expression-enhanced p38 mitogen-activated protein kinase phosphorylation. Reduced HO-1 expression sensitized MM cells to lenalidomide. Therefore, we postulated that IL-6 in the bone marrow microenvironment of MM patients stimulated high HO-1 expression in MM cells and their resistance to lenalidomide. High HO-1 expression also stimulated autocrine IL-6 production, and exacerbated drug resistance and disease. This study supports the use of HO-1 as a possible marker for both MM prognosis and drug resistance, and as a potential therapeutic target.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Talidomida
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Interleucina-6
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Resistencia a Medicamentos Antineoplásicos
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Heme Oxigenase-1
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Mieloma Múltiplo
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
FEBS J
Assunto da revista:
BIOQUIMICA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
China