Aggresome Disruption: A Novel Strategy to Enhance Bortezomib-Induced Apoptosis in Pancreatic Cancer Cells

Abstract

The proteasome inhibitor bortezomib ( formerly known as PS-341) recently received Food and Drug Administration approval for the treatment of multiple myeloma, and its activity is currently being evaluated in solid tumors. Bortezomib triggers apoptosis in pancreatic cancer cells, but the mechanisms involved have not been fully elucidated. Here, we show that pancreatic cancer cells exposed to bortezomib formed aggregates of ubiquitin-conjugated proteins (''aggresomes'') in vitro and in vivo. Bortezomib-induced aggresome formation was determined to be cytoprotective and could be disrupted using histone deacetylase (HDAC) 6 small interfering RNA or chemical HDAC inhibitors, which resulted in endoplasmic reticulum stress and synergistic levels of apoptosis in vitro and in an orthotopic pancreatic cancer xenograft model in vivo. Interestingly, bortezomib did not induce aggresome formation in immortalized normal human pancreatic epithelial cells in vitro or in murine pancreatic epithelial cells in vivo. In addition, these cells did not undergo apoptosis following treatment with bortezomib, suberoylanilide hydroxamic acid, or the combination, showing tumor selectivity. Taken together, our study shows that inhibition of aggresome formation can strongly potentiate the efficacy of bortezomib and provides the foundation for clinical trials of bortezomib in combination with HDAC inhibitors for the treatment of pancreatic cancer.

Bortezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells

“…Candidates include inhibition of nuclear factor-nB (39,46), p53 activation (18), production of reactive oxygen species (47 -49), and the accumulation of misfolded and/or damaged proteins resulting in a phenomenon termed ''endoplasmic reticulum stress'' (50 -54). With respect to the latter, our group and another found that, like tumor necrosis factor -related apoptosis-inducing ligand, histone deacetylase inhibitors synergize with bortezomib to promote cell death by enhancing the effects of bortezomib on endoplasmic reticulum stress (51,52).…”

Ubiquitylated Tax targets and binds the IKK signalosome at the centrosome

“…Finally, prolonged exposure of HuT-102 cells to PS-341 resulted in accumulation of mono-and poly-ubiquitylated endogenous Tax (Figure 6g). Upon proteasome inhibition, poly-ubiquitylated proteins are targeted by the histone deacetylase 6 to aggresome-mediated degradation (Nawrocki et al, 2006). We found that stabilization of poly-ubiquitylated Tax was significantly enhanced by the co-treatment with PS-341 and the histone deacetylase inhibitor, valproic acid and was maintained in the presence of cycloheximide (Figure 6g).…”

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

“…In multiple myeloma (83), mantle cell lymphoma (38), CML (83), and non-small cell lung cancer (21), oxidative stress is seen with the boretzomib=vorinostat combination. Reports of synergistic cell death extend to additional cell-line models including pancreatic cancer (76), hepatomas (25), and MDS (30). Aside from bortezomib, other proteasome inhibitors such as NPI-0052 also synergize with HDAC inhibitors.…”