Notch Activation by Dll1 Simulation Induces Drug Resistance in Multiple Myeloma
Drug resistance is one of the major problems in multiple myeloma (MM) clinical treatment. It is reported that Notch pathway was involved in drug resistance. In this study, we demonstrated that Notch activation by Dll1 simulation could induce drug resistance to bortezomib in murine and human MM cells. Blocking Notch pathway by DAPT (Notch inhibitor) could reverse the effect and increased the sensitivity to bortezomib. Notch activation decreased the cell apoptosis which was induced by bortezomib treatment as measured by flow cytometry. Further investigation showed that Dll1 simulation could down-regulate CD138, Blimp-1 and XBP-1 mRNA expression and shifts MM cells to a more resistant CD138- phenotype with a significant increase of CD138- subpopulation as detected by flow cytometry both in murine and human MM cells. Meanwhile, by MACS and FACS sorting of CD138+ subpopulation, we found that Notch activation could up-regulates anti-apoptotic proteins (Bcl-xL, Mcl-1 and Bcl-2) in CD138+ MM subpopulation, which also contribute to Notch activation mediated drug resistance. In a whole, on the one hand, Notch activation increases the percentage of resistant CD138- cells by down-regulating CD138, Blimp-1 and XBP-1 expression; on the other hand, Notch activation mainly up-regulates several anti-apoptotic proteins in CD138+ subpopulation, thus resulting in drug resistance to bortezomib in murine and human MM cells. Our data indicates a potential application of Notch pathway inhibitor to increase drug sensitivity to chemotherapy.
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