Molecular Sequelae of Proteasome Inhibition in Human Multiple Myeloma Cells

The proteasome inhibitor PS-341 inhibits IκB degradation, prevents NF-κB 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-induce...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2002-10, Vol.99 (22), p.14374-14379
Main Authors: Mitsiades, Nicholas, Mitsiades, Constantine S., Poulaki, Vassiliki, Chauhan, Dharminder, Fanourakis, Galinos, Gu, Xuesong, Bailey, Charles, Joseph, Marie, Libermann, Towia A., Treon, Steven P., Munshi, Nikhil C., Richardson, Paul G., Hideshima, Teru, Anderson, Kenneth C.
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Apoptosis
Biological Sciences
Boronic Acids - pharmacology
Bortezomib
Cancer
Cell growth
Cells
Cysteine Endopeptidases
Cysteine Proteinase Inhibitors - pharmacology
Cytochromes
Down regulation
Gene Expression Profiling
Heat-Shock Proteins - genetics
Humans
Insulin-Like Growth Factor I - pharmacology
Medical research
Molecules
Multienzyme Complexes - antagonists & inhibitors
Multiple Myeloma
Proteasome Endopeptidase Complex
Protein-Serine-Threonine Kinases
Proteins
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Pyrazines - pharmacology
Shock heating
Signal Transduction - drug effects
Transcription, Genetic - drug effects
Transcriptional regulatory elements
Tumor Cells, Cultured
Tumors
Ubiquitin - metabolism
Up regulation
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Summary:The proteasome inhibitor PS-341 inhibits IκB degradation, prevents NF-κB 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.202445099