Mesenchymal stem cells derived from multiple myeloma patients protect against chemotherapy through autophagy-dependent activation of NF-κB signaling

• Published in: Leukemia research 2017-09, Vol.60, p.82-88
• Main Authors: Yang, HongLiang, Zheng, YingChun, Zhang, YiZhuo, Cao, Zeng, Jiang, Yingzhe
• Format: Article
• Language: English
• Subjects: Apoptosis; Autophagy; Cell Line, Tumor; Drug resistance; Drug Resistance, Neoplasm; Humans; Mesenchymal Stromal Cells - pathology; MSCs; Multiple Myeloma - pathology; NF-kappa B - metabolism; Signal Transduction
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2017.07.002

•MM-MSCs decreased drugs-induced cell cycle arrest and apoptosis in MM cells.•MM-MSCs promote the expressions of autophagy related genes by the NF-κB signaling.•The inhibition of MM-MSCs-induced autophagy may combat chemotherapy resistance. Chemotherapy resistance has been considered as a major problem for multiple myeloma (MM) treatment and bone marrow microenvironment plays a crucial role in the MM progression and chemoresistance. Recent studies reported that bone marrow mesenchymal stem cells derived from MM patients (MM-MSCs) revealed various characteristics compared with these from healthy subjects (NM-MSCs). However, the functions and mechanisms by which MM-MSCs mediate the chemotherapy resistance of MM remain unclear. In this study, we show that MM-MSCs decreased melphalan or doxorubicin-induced cell cycle arrest and apoptosis in two MM cell lines (U266 and RPMI-8226). Mechanistically, we demonstrate that MM-MSCs promote the expressions of autophagy related genes to activate autophagy, followed by ultimately NF-κB signaling activation in MM cells. Inhibition of NF-κB signaling reversed the protective effects of MM-MSC on MM cells. Moreover, autophagy inhibitor chloroquine (CQ) or 3-Methyladenine (3MA) treatment significantly suppressed phosphorylation and consequently degradation of NF-κB inhibitor I-κBα, reduced MM-MSCs-mediate activation of NF-κB and prevented MM-MSCs-induced resistance. Taken together, our findings indicate MM-MSCs are involved in the mechanism of the chemotherapy resistance of MM. Therefore, the inhibition of MM-MSCs-induced autophagy may combat chemotherapy resistance and provide a promising therapeutic strategy for MM treatment.