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Ubiquitin proteasome system stress underlies synergistic killing of ovarian cancer cells by bortezomib and a novel HDAC6 inhibitor.

ABSTRACT: Elevated metabolic activity of ovarian cancer cells causes increased ubiquitin-proteasome-system (UPS) stress, resulting in their greater sensitivity to the toxic effects of proteasomal inhibition. The proteasomes and a potentially compensatory histone deacetylase 6 (HDAC6)-dependent lysosomal pathway mediate eukaryotic protein turnover. We hypothesized that up-regulation of the HDAC6-dependent lysosomal pathway occurs in response to UPS stress and proteasomal inhibition, and thus, ovarian cancer cell death can be triggered most effectively by coinhibition of both the proteasome- and HDAC6-dependent protein degradation pathways.To address this hypothesis, we examined HDAC6 expression patterns in normal and cancerous ovarian tissues and used a novel HDAC6-specific inhibitor, NK84, to address HDAC6 function in ovarian cancer.Abnormally high levels of HDAC6 are expressed by ovarian cancer cells in situ and in culture relative to benign epithelium and immortalized ovarian surface epithelium, respectively. Specific HDAC6 inhibition acts in synergy with the proteasome inhibitor Bortezomib (PS-341) to cause selective apoptotic cell death of ovarian cancer cells at doses that do not cause significant toxicity when used individually. Levels of UPS stress regulate the sensitivity of ovarian cancer cells to proteasome/HDAC6 inhibition. Pharmacologic inhibition of HDAC6 also reduces ovarian cancer cell spreading and migration consistent with its known function in regulating microtubule polymerization via deacetylation of alpha-tubulin.Our results suggest the elevation of both the proteasomal and alternate HDAC6-dependent proteolytic pathways in ovarian cancer and the potential of combined inhibition of proteasome and HDAC6 as a therapy for ovarian cancer.

SUBMITTER: Bazzaro M

PROVIDER: S-EPMC2744414 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Ubiquitin proteasome system stress underlies synergistic killing of ovarian cancer cells by bortezomib and a novel HDAC6 inhibitor.

Bazzaro Martina M Lin Zhenhua Z Santillan Antonio A Lee Michael K MK Wang Mei-Cheng MC Chan Kwun C KC Bristow Robert E RE Mazitschek Ralph R Bradner James J Roden Richard B S RB

Clinical cancer research : an official journal of the American Association for Cancer Research 20081101 22

<h4>Purpose</h4>Elevated metabolic activity of ovarian cancer cells causes increased ubiquitin-proteasome-system (UPS) stress, resulting in their greater sensitivity to the toxic effects of proteasomal inhibition. The proteasomes and a potentially compensatory histone deacetylase 6 (HDAC6)-dependent lysosomal pathway mediate eukaryotic protein turnover. We hypothesized that up-regulation of the HDAC6-dependent lysosomal pathway occurs in response to UPS stress and proteasomal inhibition, and thu ...[more]

PMID: 19010849

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Project description:Streptococcus pneumoniae (pneumococcus) is a Gram-positive bacterium that causes serious invasive diseases, such as pneumonia, bacteremia, and meningitis, with high morbidity and mortality throughout the world. Before causing invasive disease, S. pneumoniae encounters cellular barriers, which are often composed of endothelial cells, like the alveolar-capillary barrier and the blood-brain barrier. S. pneumoniae adheres to endothelial cells and may invade them, which requires an efficient host response to the intracellular bacteria. The precise intracellular fate of S. pneumoniae during infection still remains a subject of debate. The proteasome-ubiquitin system is largely responsible for the degradation of misfolded, damaged, or no-longer-useful proteins. Recently, the role of the proteasome-ubiquitin system in the clearing of invading bacteria and viruses has been more closely studied. In this study, we show that inhibition of the proteasome-ubiquitin system leads to a marked increase in S. pneumoniae survival inside host cells. Immunofluorescence analysis showed that intracellular pneumococci colocalized with proteasome and ubiquitin in human endothelial cells in vitro. Confocal imaging analysis demonstrated that in the brains of mice intravenously infected with S. pneumoniae, the bacteria were inside endothelial cells, where they colocalized with proteasome and ubiquitin signals. In conclusion, our data indicate that a fully functional proteasome-ubiquitin system in endothelial cells is crucial for efficient killing of intracellular S. pneumoniae. Importance: Bacterial meningitis is a serious invasive disease with high morbidity and mortality. How bacteria traverse the blood-brain barrier in vivo and what mechanisms are employed by the host to prevent invasion are still unclear. Our data show that inhibition of the proteasome-ubiquitin system in vitro leads to a significant increase in S. pneumoniae survival inside brain endothelial cells. Confocal imaging analysis of brain tissue from mice intravenously infected with pneumococci demonstrated that the bacteria are inside brain microvascular endothelial cells, where they associate with the proteasome and ubiquitin. This is, as far as we know, the first report that demonstrates that Streptococcus pneumoniae invades endothelial cells of the blood-brain barrier in vivo. The host requires the proteasome-ubiquitin system for an efficient decimation of intracellular S. pneumoniae.

Dataset Information

Ubiquitin proteasome system stress underlies synergistic killing of ovarian cancer cells by bortezomib and a novel HDAC6 inhibitor.

Publications

Ubiquitin proteasome system stress underlies synergistic killing of ovarian cancer cells by bortezomib and a novel HDAC6 inhibitor.

Similar Datasets

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