scholarly journals Beclin 1 Enhances Proteasome Inhibition-Mediated Cytotoxicity of Thyroid Cancer Cells in Macroautophagy-Independent Manner

2013 ◽  
Vol 98 (2) ◽  
pp. E217-E226 ◽  
Author(s):  
Hai-Yan Zhang ◽  
Zhen-Xian Du ◽  
Xin Meng ◽  
Zhi-Hong Zong ◽  
Hua-Qin Wang
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Essential Gene ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Beclin 1 ◽  
Independent Manner ◽  
Ubiquitin Proteasome ◽  
Thyroid Cancer Cells

Abstract Context: The ubiquitin–proteasome system and macroautophagy are two major pathways for intracellular protein degradation. Emerging lines of evidence have shown that blockade of ubiquitin–proteasome system by proteasome inhibitors activates macroautophagy. Objective: The purpose of this study was to determine the involvement of autophagy essential gene Beclin 1 in cytotoxicity of thyroid cancer cells mediated by proteasome inhibitors. Design: Autophagy was measured by acidic-trophic dye staining and EGF-LC3 distribution using fluorescence microscopy, as well as LC3-II transition using Western blot. To ascertain the effect of Beclin 1, cells were transfected with Beclin 1 plasmid or shRNA against Beclin 1. Cell viability and apoptotic cells were measured using MTT assay and flow cytometry, respectively. Results: Proteasome inhibitors decreased Beclin 1 expression. In addition, treatment with PI3K inhibitors 3-MA or wortmannin, as well as knockdown of Beclin 1 expression, was unable to affect autophagic responses mediated by proteasome inhibitors. Overexpression of Beclin 1 enhanced proteasome inhibitor–mediated cytotoxicity of thyroid cancer cells via suppression of survivin. Conclusions: Proteasome inhibitors cause Beclin 1–independent macroautophagic responses of thyroid cancer cells in a Beclin 1–independent manner. Beclin 1 possesses autophagy-independent antitumoral effects upon exposure of thyroid cancer cells to proteasome inhibitors.

scholarly journals Implication of Oxygen-Regulated Protein 150 (ORP150) in Apoptosis Induced by Proteasome Inhibitors in Human Thyroid Cancer Cells

2010 ◽  
Vol 31 (5) ◽  
pp. 779-780
Author(s):  
Yan-Yan Gao ◽  
Bao-Qin Liu ◽  
Zhen-Xian Du ◽  
Hai-Yan Zhang ◽  
Xiao-Fang Niu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Thyroid Cancer ◽  
Cancer Cells ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
26S Proteasome ◽  
Human Thyroid ◽  
Induced Apoptosis ◽  
Thyroid Cancer Cells

ABSTRACT Context The inhibition of the 26S proteasome may lead to endoplasmic reticulum stress, which has been shown to be implicated in the antitumoral effects of proteasome inhibitors. Oxygen-regulated protein 150 (ORP150) is an inducible endoplasmic reticulum chaperone that is up-regulated after numerous cellular insults and has a cytoprotective role for the maintenance of cellular viability. Objective The purpose of this study was to determine the involvement of ORP150 in cytotoxicity of thyroid cancer cells mediated by proteasome inhibition. Design The effects of proteasome inhibition on the expression of ORP150 were analyzed using real-time RT-PCR and Western blot. To ascertain the effect of ORP150, cells were transfected with ORP150 plasmid or small interfering RNA (siRNA) against ORP150, apoptotic cells, and induction of CCAAT/enhancer-binding protein homologous transcription factor (CHOP) mediated by proteasome inhibition were investigated. Results ORP150 was induced in thyroid cancer cells after proteasome inhibition. Suppression of activating transcription factor 4 expression by siRNA inhibited the up-regulation of ORP150 mediated by proteasome inhibitors. siRNA for ORP150 stimulated MG132-mediated apoptosis and induction of CHOP, a transcription factor with apoptosis-inducing activity. In contrast, ORP150-overexpressing cells demonstrated less susceptibility to MG132-induced apoptosis and displayed less up-regulation of CHOP. In addition, the sensitizing effect of small interfering ORP150 on apoptosis was suppressed by siRNA for CHOP. Conclusions These results suggest that up-regulation of ORP150 in thyroid cancer cells inhibits MG132-induced apoptosis via suppression of CHOP induction, thereby decreasing the potential antitumor activity of MG132.

scholarly journals Different Induction of GRP78 and CHOP as a Predictor of Sensitivity to Proteasome Inhibitors in Thyroid Cancer Cells

Endocrinology ◽  
2007 ◽  
Vol 148 (7) ◽  
pp. 3258-3270 ◽  
Author(s):  
Hua-Qin Wang ◽  
Zhen-Xian Du ◽  
Hai-Yan Zhang ◽  
Da-Xin Gao
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Sensitive Cell ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Thyroid Cancer Cells

Proteasome inhibitors represent a novel class of antitumor agents with preclinical and clinical evidence of activity against hematological malignancies and solid tumors. Emerging lines of evidence suggest that the unfolded protein response is implicated in proteasome inhibitors-induced apoptosis. Glucose-regulated protein 78 kDa (GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) as part of the unfolded protein response play critical roles in cell survival or death. Here we demonstrate that induction of GRP78 and CHOP are differently regulated upon proteasome inhibition in different thyroid cancer cell lines, and GRP78 levels as well as preferential induction of GRP78 or CHOP appears to be involved in the responsiveness. Insensitive ARO, 8305C, and 8505C cell lines inherently express relatively high levels of GRP78 compared with sensitive cell lines, and its levels are further up-regulated upon treatment with proteasome inhibitors. CHOP levels are dramatically induced in sensitive cell lines until 24 h after proteasome inhibition. On the other hand, only a slight increase is observed at 4 h in insensitive cell lines, and this increase is unable to be detected after 8 h. Insensitive cells are sensitized to proteasome inhibition by suppression of GRP78. Furthermore, suppression of CHOP induction or overexpression of GRP78 partially prevents proteasome inhibition-mediated cell death. Our study indicates a molecular mechanism by which the sensitivity of thyroid cancer cells is regulated by the level of GRP78 as well as preferential induction of GRP78 or CHOP upon treatment with proteasome inhibitors. Our experiments therefore suggest a novel approach toward sensitization of thyroid cancer cells to proteasome inhibitors.

scholarly journals Proteasome Inhibition Induces a p38 MAPK Pathway-Dependent Antiapoptotic Program via Nrf2 in Thyroid Cancer Cells

Endocrinology ◽  
2011 ◽  
Vol 152 (4) ◽  
pp. 1722-1724
Author(s):  
Zhen-Xian Du ◽  
Ying Yan ◽  
Hai-Yan Zhang ◽  
Bao-Qin Liu ◽  
Yan-Yan Gao ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Clinical Endocrinology ◽  
Proteasome Inhibition ◽  
P38 Mapk Pathway ◽  
Thyroid Cancer Cells

This article appears in The Journal of Clinical Endocrinology & Metabolism, published February 23, 2011, 10.1210/jc.2010-2642

scholarly journals Proteasome Inhibition Induces a p38 MAPK Pathway-Dependent Antiapoptotic Program via Nrf2 in Thyroid Cancer Cells

2011 ◽  
Vol 96 (5) ◽  
pp. E763-E771 ◽  
Author(s):  
Zhen-Xian Du ◽  
Ying Yan ◽  
Hai-Yan Zhang ◽  
Bao-Qin Liu ◽  
Yan-Yan Gao ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Proteasome Inhibition ◽  
P38 Mapk Pathway ◽  
Thyroid Cancer Cells

scholarly journals Implication of Oxygen-Regulated Protein 150 (ORP150) in Apoptosis Induced by Proteasome Inhibitors in Human Thyroid Cancer Cells

Endocrinology ◽  
2010 ◽  
Vol 151 (9) ◽  
pp. 4596-4596
Author(s):  
Yan-Yan Gao ◽  
Bao-Qin Liu ◽  
Zhen-Xian Du ◽  
Hai-Yan Zhang ◽  
Xiao-Fang Niu ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Proteasome Inhibitors ◽  
Clinical Endocrinology ◽  
Human Thyroid ◽  
Thyroid Cancer Cells

This article appears in The Journal of Clinical Endocrinology & Metabolism. 10.1210/jc.2010-1043

Drug discovery and assay development in the ubiquitin–proteasome system

2010 ◽  
Vol 38 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Celia R. Berkers ◽  
Huib Ovaa
Keyword(s):  
Proteasome Inhibitor ◽  
Clinical Success ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Clinical Use ◽  
Normal Cells ◽  
Clinical Resistance ◽  
Ubiquitin Proteasome ◽  
New Strategies

The observation that tumour cells are more sensitive to pharmacological inhibition of the proteasome than normal cells has led to the development of the proteasome inhibitor bortezomib. To date, this is the only proteasome inhibitor that has been approved for clinical use. The clinical success of bortezomib, combined with the occurrence of adverse effects and the development of clinical resistance against this compound, has initiated the development of a broad range of second-generation proteasome inhibitors as well as of assays that can be used to establish a relationship between the extent and type of proteasome inhibition and the effectiveness of a particular drug. In the present paper, we discuss new strategies that may be used in the future to overcome drug resistance and to broaden the use of proteasome inhibitors for the treatment of both cancer and infectious and autoimmune disease.

scholarly journals Proteasome inhibition in multiple myeloma: lessons for other cancers

2020 ◽  
Vol 318 (3) ◽  
pp. C451-C462 ◽  
Author(s):  
Paula Saavedra-García ◽  
Francesca Martini ◽  
Holger W. Auner
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
26S Proteasome ◽  
Cellular Functions ◽  
Glucose And Lipid Metabolism ◽  
Ubiquitin Proteasome ◽  
Cancer Multiple

Cellular protein homeostasis (proteostasis) depends on the controlled degradation of proteins that are damaged or no longer required by the ubiquitin-proteasome system (UPS). The 26S proteasome is the principal executer of substrate-specific proteolysis in eukaryotic cells and regulates a myriad of cellular functions. Proteasome inhibitors were initially developed as chemical tools to study proteasomal function but rapidly became widely used anticancer drugs that are now used at all stages of treatment for the bone marrow cancer multiple myeloma (MM). Here, we review the mechanisms of action of proteasome inhibitors that underlie their preferential toxicity to MM cells, focusing on endoplasmic reticulum stress, depletion of amino acids, and effects on glucose and lipid metabolism. We also discuss mechanisms of resistance to proteasome inhibition such as autophagy and metabolic rewiring and what lessons we may learn from the success and failure of proteasome inhibition in MM for treating other cancers with proteostasis-targeting drugs.

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