Bone marrow mesenchymal stem cell derived exosomal miR-361-5p reversed the effect of bortezomib on multiple myeloma

Abstract

BackgroundBortezomib is the first-line drug in the treatment of multiple myeloma (MM) and its resistance is the main obstacle to cure MM. MicroRNA-361-5p (MiRNA-361-5p) in bone marrow mesenchymal stem cells (BMSCs) might participate in the bortezomib resistance via paracrine pathway. The study was to characterize the role and molecular mechanism of miR-361-5p in bortezomib resistance in MM.MethodsThe exosomes of BMSCs were obtained and characterized by transmission electron microscopy and nanoparticle tracking analysis. The MM cell U266 was treated with bortezomib, bortezomib and BMSC exosomes, bortezomib and BMSC exosomes transfected with miR-361-5p inhibitor. The cell viability was measured by cell counting kit. Protein expression of PDPK1, PI3K, p-PI3K, mTOR, p-mTOR, AKT, and Pan-AKT was detected by western blot. The apoptosis level of bortezomib resistant cell lines was detected by flow cytometry.ResultsLow expression of miR-361-5p promoted the survival of U266 cells and inhibited cell apoptosis, reversing the inhibitory effect of bortezomib on U266 cells. PDPK1 may be a downstream target of miR-361-5p. Low expression of BMSCs-derived exosomal miR-361-5p may reverse the effect of bortezomib on U266 cells by regulating the PDPK1/PI3K/AKT/mTOR axis.ConclusionLow expression of BMSCs-derived exosomal miR-361-5p may overcome bortezomib resistance in MM by regulating PDPK1/PI3K/AKT/mTOR axis.

Keywords: Bone marrow mesenchymal stem cells; PDPK1; exosomes; miR-361-5p; multiple myeloma.