1. Molecular sequelae of proteasome inhibition in human multiple myeloma cells.
- Author
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Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Treon SP, Munshi NC, Richardson PG, Hideshima T, and Anderson KC
- Subjects
- Bortezomib, Cysteine Endopeptidases, Down-Regulation, Gene Expression Profiling, Heat-Shock Proteins genetics, Humans, Insulin-Like Growth Factor I pharmacology, Multiple Myeloma, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt, Transcription, Genetic drug effects, Tumor Cells, Cultured, Ubiquitin metabolism, Antineoplastic Agents pharmacology, Apoptosis, Boronic Acids pharmacology, Cysteine Proteinase Inhibitors pharmacology, Multienzyme Complexes antagonists & inhibitors, Protein Serine-Threonine Kinases, Pyrazines pharmacology, Signal Transduction drug effects
- Abstract
The proteasome inhibitor PS-341 inhibits IkappaB degradation, prevents NF-kappaB activation, and induces apoptosis in several types of cancer cells, including chemoresistant multiple myeloma (MM) cells. PS-341 has marked clinical activity even in the setting of relapsed refractory MM. However, PS-341-induced apoptotic cascade(s) are not yet fully defined. By using gene expression profiling, we characterized the molecular sequelae of PS-341 treatment in MM cells and further focused on molecular pathways responsible for the anticancer actions of this promising agent. The transcriptional profile of PS-341-treated cells involved down-regulation of growth/survival signaling pathways, and up-regulation of molecules implicated in proapoptotic cascades (which are both consistent with the proapoptotic effect of proteasome inhibition), as well as up-regulation of heat-shock proteins and ubiquitin/proteasome pathway members (which can correspond to stress responses against proteasome inhibition). Further studies on these pathways showed that PS-341 decreases the levels of several antiapoptotic proteins and triggers a dual apoptotic pathway of mitochondrial cytochrome c release and caspase-9 activation, as well as activation of Jun kinase and a Fas/caspase-8-dependent apoptotic pathway [which is inhibited by a dominant negative (decoy) Fas construct]. Stimulation with IGF-1, as well as overexpression of Bcl-2 or constitutively active Akt in MM cells also modestly attenuates PS-341-induced cell death, whereas inhibitors of the BH3 domain of Bcl-2 family members or the heat-shock protein 90 enhance tumor cell sensitivity to proteasome inhibition. These data provide both insight into the molecular mechanisms of antitumor activity of PS-341 and the rationale for future clinical trials of PS-341, in combination with conventional and novel therapies, to improve patient outcome in MM.
- Published
- 2002
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