Molecular sequelae of proteasome inhibition in human multiple myeloma cells.
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.
Mitsiades
Nicholas
N
Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Mitsiades
Constantine S
CS
Poulaki
Vassiliki
V
Chauhan
Dharminder
D
Fanourakis
Galinos
G
Gu
Xuesong
X
Bailey
Charles
C
Joseph
Marie
M
Libermann
Towia A
TA
Treon
Steven P
SP
Munshi
Nikhil C
NC
Richardson
Paul G
PG
Hideshima
Teru
T
Anderson
Kenneth C
KC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006360:Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D009101:Multiple Myeloma; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D015853:Cysteine Proteinase Inhibitors; D006360:Heat-Shock Proteins; D009097:Multienzyme Complexes; D011518:Proto-Oncogene Proteins; D011719:Pyrazines; D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; D000069286:Bortezomib; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex