Proteomic and functional analyses reveal a dual molecular mechanism underlying arsenic-induced 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. In the present study, we used proteomics to analyze the ATO-induced protein alterations in MM cell line U266 and then investigated the molecular pathways responsible for the anticancer actions of ATO. 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. Significantly regulated 14-3-3zeta and heat shock proteins (HSPs) were selected for further functional studies. Overexpression of 14-3-3zeta in MM cells attenuated ATO-induced cell death, whereas RNAi-based 14-3-3zeta knock-down or the inhibition of HSP90 enhanced tumor cell sensitivity to the ATO induction. These observations implicate 14-3-3zeta and HSP90 as potential molecular targets for drug intervention of multiple myeloma and thus improve our understanding on the mechanisms of antitumor activity of ATO.
Ge
Feng
F
Institute of Life and Health Engineering, Jinan University, Guangzhou 510632, China.
Lu
Xin-Peng
XP
Zeng
Hui-Lan
HL
He
Quan-Yuan
QY
Xiong
Sheng
S
Jin
Lin
L
He
Qing-Yu
QY
D048948:14-3-3 Proteins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015180:Electrophoresis, Gel, Two-Dimensional; D055785:Gene Knockdown Techniques; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010087:Oxides / Q000494:pharmacology*; D025941:Protein Interaction Mapping; D020543:Proteome; D040901:Proteomics / Q000379:methods*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013312:Stress, Physiological; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D001152:Arsenicals; D018841:HSP90 Heat-Shock Proteins; D010087:Oxides; D020543:Proteome; D034741:RNA, Small Interfering; D043743:Ubiquitin-Protein Ligase Complexes; D000077237:Arsenic Trioxide