Bortezomib-Induced Survival Signals and Genes in Human Proximal Tubular Cells

作者：Sarkoezi Rita; Perco Paul; Hochegger Kathrin; Enrich Julia; Wiesinger Martin; Pirklbauer Markus; Eder Susanne; Rudnicki Michael; Rosenkranz Alexander R; Mayer Bernd; Mayer Gert; Schramek Herbert^*

来源：Journal of Pharmacology and Experimental Therapeutics, 2008, 327(3): 645-656.

DOI：10.1124/jpet.108.142604

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 I kappa B-alpha and to a long-lasting phosphorylation of both NF-kappa Bp65 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-kappa B activation and cell survival should be carefully examined in particular renal cell types.

• 出版日期2008-12