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

Abstract 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.