Bortezomib-induced survival signals and genes in human proximal tubular cells.
Bortezomib has been introduced recently in the therapy of multiple myeloma (MM), a disease that is frequently associated with progressive renal failure. Because bortezomib-based therapy has been reported to lead to a rapid recovery of kidney function in patients with MM, we decided to study its direct effects in proximal tubular epithelial cells (PTCs) compared with glomerular mesangial cells (GMCs). After 24 h of stimulation, 50 nM bortezomib led to a 6.37-fold induction of apoptosis and markedly activated caspase-9 and -3 in GMCs but not in PTCs. In PTCs but not in GMCs, bortezomib led to a strong time-dependent degradation of IkappaB-alpha and to a long-lasting phosphorylation of both NF-kappaBp65 and extracellular signal-regulated kinase 1/2. Microarray analysis in bortezomib-treated PTCs revealed a time-dependent predominance of antiapoptotic genes compared with proapoptotic genes. Bortezomib (50 nM) induced heat shock protein (Hsp) 70 mRNA and protein levels in PTCs, whereas basal and bortezomib-stimulated Hsp70 protein expression was much weaker in GMCs. Moreover, bortezomib induced Bcl-2-associated athanogene (BAG) 3 mRNA and protein expression but inhibited BAG5 mRNA levels in PTCs. These data suggest that the reduced susceptibility of PTCs to bortezomib-induced cell apoptosis is because of cell type-specific effects of this compound on apoptosis/survival genes and pathways. The concept of bortezomib representing a blocker of both NF-kappaB activation and cell survival should be carefully examined in particular renal cell types.
Sarközi
Rita
R
Division of Nephrology and Hypertension, Department of Internal Medicine IV, Innsbruck Medical University, Innsbruck, Austria.
Perco
Paul
P
Hochegger
Kathrin
K
Enrich
Julia
J
Wiesinger
Martin
M
Pirklbauer
Markus
M
Eder
Susanne
S
Rudnicki
Michael
M
Rosenkranz
Alexander R
AR
Mayer
Bernd
B
Mayer
Gert
G
Schramek
Herbert
H
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002470:Cell Survival / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D050527:Mesangial Cells / Q000166:cytology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051996:Transcription Factor RelA / Q000378:metabolism
D001897:Boronic Acids; D018840:HSP70 Heat-Shock Proteins; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D011719:Pyrazines; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D000069286:Bortezomib; D048052:Mitogen-Activated Protein Kinase 3