技术资料

Multiple myeloma (MM) cells are characterized by high protein synthesis resulting in chronic endoplasmic reticulum (ER) stress,which is adaptively managed by the unfolded protein response. Inositol-requiring enzyme 1? (IRE1?) is activated to splice X-box binding protein 1 (XBP1) mRNA,thereby increasing XBP1s protein,which in turn regulates genes responsible for protein folding and degradation during the unfolded protein response. In this study,we examined whether IRE1?-XBP1 pathway is a potential therapeutic target in MM using a small-molecule IRE1? endoribonuclease domain inhibitor MKC-3946. MKC-3946 triggered modest growth inhibition in MM cell lines,without toxicity in normal mononuclear cells. Importantly,it significantly enhanced cytotoxicity induced by bortezomib or 17-AAG,even in the presence of bone marrow stromal cells or exogenous IL-6. Both bortezomib and 17-AAG induced ER stress,evidenced by induction of XBP1s,which was blocked by MKC-3946. Apoptosis induced by these agents was enhanced by MKC-3946,associated with increased CHOP. Finally,MKC-3946 inhibited XBP1 splicing in a model of ER stress in vivo,associated with significant growth inhibition of MM cells. Taken together,our results demonstrate that blockade of XBP1 splicing by inhibition of IRE1? endoribonuclease domain is a potential therapeutic opt View Publication