Proteomic And Functional Study Of Arsenic Trioxide-mediated Apoptosis In Human Multiple Myeloma Cells

Multiple myeloma(MM) is an incurable plasma cell malignancy with a terminal phase marked by increased proliferation and resistance to therapy.Arsenic trioxide(ATO),an antitumor agent with a multifaceted mechanism of action,displayed clinical activity in patients with late-stage multiple myeloma.However,the precise mechanism(s) of action of ATO has not been completely elucidated.AIM:To use proteomics to analyze the ATO-induced protein alterations in MM cell line U266 cells to investigated the molecular pathways responsible for the anticancer actions of ATO.METHOD:We used a global proteomic-based approach to look at ATO-induced apoptosis in U266 myeloma cells.By comparing the protein,profiles of U266 cells treated by ATO to those untreated control,we identified differentially expressed proteins.Significantly regulated 14-3-3ζand heat shock proteins(HSPs) were selected for further functional studies.RESULTS:Several clusters of proteins altered in expression in U266 Cells upon ATO treatment were identified,including down-regulated signal transduction proteins and ubiquitin/proteasome members,and up-regulated immunity and defense proteins. Overexpression of 14-3-3ζin MM cells attenuated ATO-induced cell death,whereas RNAi-based 14-3-3ζknock-down or the inhibition of HSP90 enhanced U266 cell sensitivity to the ATO induction.CONCLUSIONS:The current study characterized the molecular sequelae of ATO treatment in MM and defined apoptotic pathways triggered by this agent.Our results showed that ATO induced up-regulation of HSPs and down-regulation of 14-3-3ζand the members of proteasome/ubiquitin system.Specifically,our in-depth functional studies suggested a dual apoptotic mechanism induced by ATO in MM cells,with a pivotal role for the 14-3-3ζin one arm and the regulation of ubiquitination-proteasome pathway in the other.