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 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

Ceramide-Induced Apoptosis of Human Thyroid Cancer Cells Resistant to Apoptosis by Irradiation

Thyroid ◽  
2000 ◽  
Vol 10 (9) ◽  
pp. 733-740 ◽  
Author(s):  
Yuriy Sautin ◽  
Noboru Takamura ◽  
Stanislav Shklyaev ◽  
Yuji Nagayama ◽  
Akira Ohtsuru ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Human Thyroid ◽  
Induced Apoptosis ◽  
Thyroid Cancer Cells

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 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 CRSP8 promotes thyroid cancer progression by antagonizing IKKα-induced cell differentiation

2020 ◽  
Author(s):  
Yina Liao ◽  
Yijun Hua ◽  
Yizhuo Li ◽  
Changlin Zhang ◽  
Wendan Yu ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Direct Interaction ◽  
Anaplastic Thyroid Cancer ◽  
Human Thyroid ◽  
Induced Apoptosis ◽  
Thyroid Cancer Cells

Abstract CRSP8 plays an important role in recruiting mediators to genes through direct interaction with various DNA-bound transactivators. In this study, we uncovered the unique function of CRSP8 in suppressing thyroid cancer differentiation and promoting thyroid cancer progression via targeting IKKα signaling. CRSP8 was highly expressed in human thyroid cancer cells and tissues, especially in anaplastic thyroid cancer (ATC). Knockdown of CRSP8 suppressed cell growth, migration, invasion, stemness, and induced apoptosis and differentiation in ATC cells, while its overexpression displayed opposite effects in differentiated thyroid cancer (DTC) cells. Mechanistically, CRSP8 downregulated IKKα expression by binding to the IKKα promoter region (−257 to −143) to negatively regulate its transcription. Knockdown or overexpression of IKKα significantly reversed the expression changes of the differentiation and EMT-related markers and cell growth changes mediated by CRSP8 knockdown or overexpression in ATC or DTC cells. The in vivo study also validated that CRSP8 knockdown inhibited the growth of thyroid cancer by upregulating IKKα signaling in a mouse model of human ATC. Furthermore, we found that CRSP8 regulated the sensitivity of thyroid cancer cells to chemotherapeutics, including cisplatin and epirubicin. Collectively, our results demonstrated that CRSP8 functioned as a modulator of IKKα signaling and a suppressor of thyroid cancer differentiation, suggesting a potential therapeutic strategy for ATC by targeting CRSP8/IKKα pathway.

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

2010 ◽  
Vol 95 (11) ◽  
pp. E319-E326 ◽  
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 ◽  
Human Thyroid ◽  
Thyroid Cancer Cells

scholarly journals Suppression of MG132-mediated cell death by peroxiredoxin 1 through influence on ASK1 activation in human thyroid cancer cells

2010 ◽  
Vol 17 (3) ◽  
pp. 553-560 ◽  
Author(s):  
Zhen-Xian Du ◽  
Ying Yan ◽  
Hai-Yan Zhang ◽  
Bao-Qin Liu ◽  
Yan-Yan Gao ◽  
...  
Keyword(s):  
Cell Death ◽  
Thyroid Cancer ◽  
Cancer Cells ◽  
Proteasome Inhibitor ◽  
Antitumor Agents ◽  
Proteasome Inhibitors ◽  
Hematologic Malignancies ◽  
Mitogen Activated Protein Kinase ◽  
Human Thyroid ◽  
Thyroid Cancer Cells

Proteasome inhibitors represent a novel class of antitumor agents with pre-clinical and clinical evidence of activity against hematologic malignancies and solid tumors. However, emerging evidence indicates that antiapoptotic factors may also accumulate as a consequence of exposure to these drugs, thus it seems plausible that the activation of survival signaling cascades might compromise their antitumoral effects. Peroxiredoxins (PRDXs) are a family of thiol-containing peroxidases identified primarily by their ability to remove cellular hydroperoxides. The function of PRDX1 in particular has been implicated in regulating cell proliferation, differentiation, and apoptosis. Another important finding is that aberrant upregulation of PRDX1 has been discovered in various cancers. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK) kinase kinase that is regulated under conditions of cellular stress. ASK1 phosphorylates c-Jun N-terminal kinase and p38 MAPK, and elicits an apoptotic response. ASK1 activity is regulated at multiple levels, one of which is through interaction with PRDX1. In this study, for the first time we report that upregulation of PRDX1 expression was found in thyroid cancer cells treated with proteasome inhibitors, and PRDX1 knockdown resulted in accelerated proteasome inhibitor-induced cell death. In addition, we demonstrated that ASK1 activity was implicated in the PRDX1-dependent response of thyroid cancer cells to proteasome inhibitor-mediated cell death.

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