NF-κB–independent down-regulation of XIAP by bortezomib sensitizes HL B cells against cytotoxic drugs

Abstract

IntroductionThe proteasome, a large multicatalytic proteinase complex, is responsible for the degradation of most intracellular proteins. The proteasome has a central role in catabolism of a wide variety of proteins controlling cellular division, growth, function, and death. Numerous examples of regulatory proteins including cyclins, cyclin-dependent kinases and kinase inhibitors, oncogenes, tumor suppressor genes, and transcriptional activators and inhibitors have been found to undergo proteasomal proteolysis. Inhibition of the proteasome induces the accumulation of important regulatory intracellular proteins like cytoplasmic inhibitor of NF-B (IB␣), p53 tumor suppressor gene, and p21 and p27 cyclin-dependent kinase inhibitors, which leads to decreased NF-B activity, increased p53-mediated transcription of genes involved in apoptosis, and dysregulation of the cell cycle. [1][2][3][4] In cancer cells, the proteasome is essential to mechanisms underlying tumor cell growth, apoptosis, angiogenesis, and metastasis, thereby representing a novel target for cancer therapy. [3][4][5] Pharmacologic inhibitors of the proteasome have been shown to possess antitumor activity and have significant efficacy against a variety of malignancies. 1-2 The best characterized proteasome inhibitor, bortezomib (Velcade, previously known as PS-341; Millennium Pharmaceuticals, Cambridge, MA), is a dipeptidyl boronic acid that reversibly inhibits the chymotrypsin-like activity of the proteasome. This agent displays remarkable selectivity toward the proteasome relative to serine and cysteine proteases, and it possesses unique antitumor properties as shown in a National Cancer Institute (NCI) tumor cell line screen and in several murine xenograft models. [6][7][8][9][10][11] Bortezomib is the first proteasome inhibitor that was clinically tested in patients and became a therapeutic modality for multiple myeloma.Hodgkin lymphoma (HL) accounts for approximately 30% of all malignant lymphomas 12 with the common feature that neoplastic cells constitute only a small minority of the cells in the affected tissue, often corresponding to less than 2% of the total tumor load. Classical HL (cHL), representing approximately 95% of all HLs, is a fatal disease with 90% of untreated patients dying within 2 to 3 years. 12 The tumor cells of cHL, designated Hodgkin-ReedSternberg (H-RS) cells, are mainly derived from germinal center or post-germinal center B cells, while few (less than 2%) are derived from T cells. H-RS cells lack specific functional markers of mature B or T cells, seem to be arrested in maturation, and therefore should be physiologically prone to undergo apoptosis. [13][14] The mechanisms of apoptotic resistance in H-RS cells have been intensively investigated during the last decade. It has been shown that H-RS cells are resistant to CD95-mediated apoptosis 15 due to the constitutive expression of cFLIP. 16 In addition, H-RS cells display a defective mitochondrial apoptotic pathway 17 and uniformly show up-regulated XIAP expression, 18 whic...

Sensitization of melanoma cells to TRAIL by UVB-induced and NF-κB-mediated downregulation of xIAP

“…NF-kB activation consequently resulted in the upregulation of xIAP transcription or in continued high levels of xIAP mRNA in cells showing transient and constitutive NFkB activity, as it has been described to frequently occur during melanoma progression (Ueda and Richmond, 2006). High xIAP protein levels may compensate its proteasomal degradation during induction of apoptosis (Kashkar et al, 2007). Upon TRAIL sensitization by UVB, significantly enhanced IkBa degradation coincided with a decrease in xIAP at the protein as well as the mRNA level.…”

A mitochondrial block and expression of XIAP lead to resistance to TRAIL-induced apoptosis during progression to metastasis of a colon carcinoma

“…As an attempt to inhibit XIAP expression, we used the proteasome inhibitor bortezomib that has been shown to modulate XIAP at the post-translational level in a nuclear factor (NF)-kB-independent manner (Kashkar et al, 2007). Indeed, bortezomib inhibited XIAP expression in SW620 cells after 6 h of incubation ( Figure 4b).…”

Survivin Blockade Sensitizes Rhabdomyosarcoma Cells for Lysis by Fetal Acetylcholine Receptor–Redirected T Cells

“…45 The relevance of XIAP for the execution of a T-cell attack is sustained by our previous observation that XIAPoverexpressing Hodgkin lymphoma cells were rendered susceptible to redirected T cells by XIAP knockdown. 46 In vivo analysis, using a xenograft transplant model, confirmed the relevance of survivin expression for RMS tumor cell survival and growth. Because celecoxib is associated with severe adverse effects, we used the welltolerated survivin inhibitor, SHP.…”