Blockade of SDF‐1/CXCR4 reduces adhesion‐mediated chemoresistance of multiple myeloma cells via interacting with interleukin‐6

Abstract

Resistance to chemotherapy represents a major cause for treatment failure in multiple myeloma (MM). Herein, this study was conducted to explore the effect of SDF-1/CXCR4 and interleukin-6 (IL-6) in MM cell adhesion-mediated chemoresistance. Enzyme-linked immunosorbent assay was applied to detect expressions of SDF-1α and IL-6 in MM patients and healthy controls. RPMI-8226 cells and isolated bone marrow stromal cells (BMSCs) were stimulated using recombinant SDF-1α and IL-6. Effect of cocultured BMSCs and RPMI-8226 cells on chemosensitivity and apoptosis of RPMI-8226 cells was analyzed. Effect of doxorubicin on the adhesion rate of RPMl-8226 cells to BMSCs was analyzed by calcitonin test. Effect of SDF-1αinduced upregulation of IL-6 on chemotherapeutic resistance and apoptosis of RPMI-8226 cells in adhesion state was analyzed. Cell adhesion model was treated with recombinant protein SDF-1α and phosphoinositide 3-kinase (P13K) inhibitor Wortmarmin. The levels of P13K and protein kinase B (AKT) and its phosphorylation as well as the expression of IL-6 were analyzed. SDF-1α was positively correlated with IL-6. Recombinant human SDF-1α increased IL-6 expression and induced IL-6 secretion in a time-and dose-dependent manner in BMSCs, which was inhibited by IL-6 and SDF-1α neutralizing antibodies. Coculture of MM cells with BMSCs increased the drug resistance and inhibited the apoptosis on MM cells. SDF-1αinduced IL-6 upregulation mediates chemoresistance and apoptosis of RPMI-8226 cells in adhesion state. SDF-1α may up-regulate the expression of IL-6 by activating the P13K/AKT signaling pathway. SDF-1/CXCR4 may up-regulate the expression of IL-6 through the activation of the P13K/AKT signaling pathway, thereby affecting the chemoresistance mediated by adhesion in MM cells.

Multiple Myeloma Cells Alter Adipogenesis, Increase Senescence-Related and Inflammatory Gene Transcript Expression, and Alter Metabolism in Preadipocytes

“…For example, targeting IL6 (e.g., Johnson and Johnson’s drug sirukumab), or the IL6 receptor (e.g., Regeneron’s sarilumab) could be tailored perhaps by using BMAT biomarkers ( 62 ), knowing now that BMAds, especially myeloma-associated adipocyte lineage cells, are a source of IL6. Better alignment with patient populations for enhanced precision medicine could also be considered based on our data, for therapies targeting the CXCL12/CXCR4 axis, such as the CXCR4 inhibitor AMD3100 (plerixafor) ( 63 ), or the CXCL12 antagonist NOX-A12 ( 64 ). Our data may also help explain the ability of treatment with plerixafor to overcome bortezomib resistance and mobilize stem cells and immune cells, which was recently reported in a phase I/II trial ( 65 ), by providing new insight into the players in the bone marrow niche involved in this pathway.…”

“…Our data may also help explain the ability of treatment with plerixafor to overcome bortezomib resistance and mobilize stem cells and immune cells, which was recently reported in a phase I/II trial ( 65 ), by providing new insight into the players in the bone marrow niche involved in this pathway. Interestingly, new data in vitro has shown that SDF-1α stimulation of CXCR4 on MM cells may up-regulate the expression of IL-6 through the activation of the PI3K/AKT, suggesting that the IL6 and CXCR4/CXCL12 pathways overlap in MM cells ( 64 ). Overall, our study provides insight into the mechanism of action of drugs targeting the CXCL12/CXCR4 axis, the IL6/IL6R axis, or other SASP protein signaling pathways in MM, and suggests that targeting proteins identified herein may lead to new therapeutic avenues.…”

Role and Therapeutic Targeting of SDF-1α/CXCR4 Axis in Multiple Myeloma

“…The coculture of MM cells with BMSCs increased the drug resistance and suppressed the cell death of MM cells. Consequently, Liu et al demonstrated that SDF-1α-induced interleukin-6 (IL-6) upregulation-mediated drug resistance and apoptosis of MM cell lines in the adhesion state [56]. The report mentioned that SDF-1α treatment-induced PI3K and AKT phosphorylation in MM cells.…”

Updates to the drug‐resistant mechanism of proteasome inhibitors in multiple myeloma

“…Recently, a study indicated that when coculture RPMl‐8226 cells with BMSCs, MM cells showed increased level of drug resistance and cell survival. It is attributed to IL‐6, which was upregulated by SDF‐1/CXCR4 causing the activation of the P13K/AKT signaling pathway, thereby affecting the drug resistance mediated by adhesion in MM cells 47 . Enhanced insulin‐like growth factor (IGF‐1) by IL‐6 upregulates MCL‐1 transcription and induces MCL‐1 dependence.…”