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Potential crosstalk of the interleukin‐6–heme oxygenase‐1‐dependent mechanism involved in resistance to lenalidomide in multiple myeloma cells
Author(s) -
Wu Weibing,
Ma Dan,
Wang Ping,
Cao Lu,
Lu Tangsheng,
Fang Qin,
Zhao Jiangyuan,
Wang Jishi
Publication year - 2016
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13633
Subject(s) - lenalidomide , heme oxygenase , crosstalk , mechanism (biology) , multiple myeloma , chemistry , cancer research , heme , microbiology and biotechnology , biology , immunology , biochemistry , physics , enzyme , quantum mechanics , optics
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 CD 138 + 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, RPMI 8226 and CD 138 + 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, RPMI 8226 and bone marrow CD 138 + 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.