Moreover and importantly, we found that BTZ-resistant MM cells have significant increases in GSH as compared with that in the drug-na?ve setting, which based on the inhibitory effects of antioxidants would suppress BTZ-induced ER stress

Moreover and importantly, we found that BTZ-resistant MM cells have significant increases in GSH as compared with that in the drug-na?ve setting, which based on the inhibitory effects of antioxidants would suppress BTZ-induced ER stress.41 In addition, we found that the BTZ-resistant phenotype is associated with downregulation of CHOP by a redox-dependent mechanism. treatment by synergistically downregulating TIGAR and GSH. The GO-203/BTZ combination is thus highly effective in killing BTZ-resistant MM PSI-6206 cells. These findings support a model in which targeting MUC1-C is synergistic with BTZ in suppressing TIGAR-mediated regulation of ROS levels and provide an experimental rationale for combining GO-203 with BTZ in certain PSI-6206 settings of BTZ resistance. Introduction Multiple myeloma (MM) is a clonal malignancy of plasma cells that is characterized in part by the abnormal synthesis and secretion of monoclonal immunoglobulins or light chains.1 Cellular homeostasis is dependent on the balanced regulation of protein synthesis and degradation, the latter of which is predominantly mediated by the ubiquitin-proteosome pathway.2 Bortezomib (BTZ) is a reversible inhibitor of the proteosome that is effective in inducing apoptosis of MM cells and is active in the treatment of this disease.1 BTZ has improved response rates of MM patients to induction therapy and is being used as consolidation after frontline treatment or transplantation.1,3 However, intrinsic and acquired resistance to BTZ represent a challenge for the treatment of MM, which remains an incurable disease.1 BTZ has been shown to activate the unfolded protein response (UPR), a pathway induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and associated with increases in reactive oxygen species (ROS).4,5 In this way, BTZ treatment of MM cells induces expression of CCAAT/enhancer binding proteinChomologous protein (CHOP; GADD153), a key transcription factor that participates in cellular responses to ER and oxidative stress.6-8 The mechanistic basis for BTZ activity has also been attributed to inhibition of inhibitory nuclear factor B (NF-B) degradation and thereby downregulation of the NF-B pathway.9,10 In addition, mechanisms potentially unrelated to the UPR and NF-B have been attributed to BTZ resistance. For example, mutations in the 5 proteosome subunit have been identified that decrease BTZ binding and sensitivity.11 Nonetheless, 5 subunit mutations have not been found in PSI-6206 patients with BTZ resistance.12 Activation of phosphatidylinositol 3-kinaseprotein kinase B signaling may also play a role in BTZ resistance in that inhibition of this pathway in MM cells contributes to BTZ sensitivity.13-15 Other studies of MM cells selected for BTZ resistance have demonstrated activation of the insulin-like growth factor-1 receptor (IGF-1R).16 In this regard, silencing IGF-1R or treatment with an IGF-1R inhibitor effectively resensitizes BTZ-resistant cell lines and patient samples to BTZ.16 Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly expressed by most MM patient samples and cell lines.17-22 However, the functional significance of MUC1 expression in MM cells remains poorly understood. Certain insights into MUC1 function have evolved from the finding that MUC1 Rabbit polyclonal to FBXW12 is translated as a single polypeptide which undergoes autocleavage into 2 subunits in the ER that, in turn, form a stable heterodimer at the cell surface.23 The MUC1 N-terminal subunit is positioned extracellularly in a complex with the transmembrane MUC1 C-terminal subunit (MUC1-C). The MUC1-C subunit includes a 72-amino-acid cytoplasmic tail that is phosphorylated by diverse kinases and thereby interacts with multiple effectors that have been linked to transformation.23,24 Moreover and in addition to its positioning at the cell membrane, MUC1-C is imported to PSI-6206 the nucleus where it interacts with transcription factors.