Abstract
The bone marrow (BM) microenvironment plays an important role in supporting proliferation, survival and drug resistance of Multiple Myeloma (MM) cells. MM cells adhere to bone marrow stromal cells leading to the activation of tumour-promoting signaling pathways. Activation of the NFκB pathway, in particular, is central to the pathogenesis of MM. Tumour necrosis factor receptor-associated factor 6 (TRAF6) is a key mediator of NFκB activation and has previously been highlighted as a potential therapeutic target in MM. Here, we demonstrate that adherence of MM cell lines to stromal cells results in a reciprocal increase in TRAF6 expression. Knockdown of TRAF6 expression attenuates the ability of MM cells to bind to stromal cells and this is associated with a decrease in NFκB-induced expression of the adhesion molecules ICAM1 and VCAM1. Finally, we show that knockdown of TRAF6 sensitizes MM cells to treatment with bortezomib when co-cultured with stromal cells. Inhibiting TRAF6 represents a promising strategy to target MM cells in the BM microenvironment.
Highlights
Multiple Myeloma (MM) is characterised by the proliferation of malignant plasma cells in the bone marrow, resulting in the excessive production of monoclonal protein in the serum and urine
Huang and colleagues recently demonstrated that bone marrow stromal cells (BMSCs) induce the expression of Tumour necrosis factor receptor-associated factor 6 (TRAF6) in MM cell lines [22]
To investigate whether TRAF6 expression is affected in BMSCs, we co-cultured KMS-11 and U266 cell lines with the human stromal cell line HS-5
Summary
Multiple Myeloma (MM) is characterised by the proliferation of malignant plasma cells in the bone marrow, resulting in the excessive production of monoclonal protein in the serum and urine. Through the upregulation of interleukin (IL)-6 and receptor activator of NFκB ligand (RANKL), BMSC–MM interactions promote the differentiation and proliferation of osteoclasts which lead to bone resorption and further promote the growth of MM cells [8,9], forming a vicious cycle of bone destruction and MM cell proliferation. It is important, to develop novel therapeutic approaches which act on MM cells and on the protective microenvironment. We sought to investigate the effect of TRAF6 silencing on MM–BMSC interactions
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