In the present study, we used a combined strategy that comprised phosphoprotein enrichment, SILAC, and LC/MS analysis to profile the differential phosphoproteome in bortezomib-treated MM cells. A total of 72 phosphoproteins were found to have a 1.5-fold or greater change upon bortezomib treatment (Table S2 ). According to their change pattern, these DEPPs can be categorized into up-(,0.75) or down-(.1.5) regulated groups (Table S2) . Notably, in comparison with the number of downregulated DEPPs, many more proteins are up-regulated in this process (70 versus 5). This unbalanced pattern has also been revealed by previous in vitro biochemical studies [22] . Many studies have demonstrated that bortezomib can trigger pleiotropic signaling pathways and suppress the proteasomal degradation of multiple phosphorylated singnaling molecules [8, 10, 31] . Therefore, we speculate that the up-regulation of phosporylation of these DEPPs may constitute one of the mechanisms of bortezomibinduced apoptosis in MM cells. The PANTHER classification system also revealed that the DEPPs implicated in a variety of molecular functions, such as nucleic acid binding, receptor, regulatory molecule and so on (Fig. 3A) , clearly showing that in addition to targeting proteins involved in apoptotic pathways, bortezomib also altered multiple signaling pathways to induce its anti-cancer effects.