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 BET Inhibitors Synergize with Carfilzomib to Induce Cell Death in Cancer Cells via Impairing Nrf1 Transcriptional Activity and Exacerbating the Unfolded Protein Response

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 501 ◽  
Author(s):  
Janakiram R. Vangala ◽  
Ajay Potluri ◽  
Senthil K. Radhakrishnan
Keyword(s):  
Unfolded Protein Response ◽  
Solid Tumors ◽  
Cell Lines ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Therapeutic Modality ◽  
Unfolded Protein ◽  
Bet Inhibitors ◽  
The Unfolded Protein Response ◽  
Protein Response

Currently, proteasome inhibitors bortezomib, carfilzomib, and ixazomib are successfully used in clinics to treat multiple myeloma. However, these agents show limited efficacy against solid tumors. Identification of drugs that can potentiate the action of proteasome inhibitors could help expand the use of this therapeutic modality to solid tumors. Here, we found that bromodomain extra-terminal (BET) family protein inhibitors such as JQ1, I-BET762, and I-BET151 synergize with carfilzomib in multiple solid tumor cell lines. Mechanistically, BET inhibitors attenuated the ability of the transcription factor Nrf1 to induce proteasome genes in response to proteasome inhibition, thus, impeding the bounce-back response of proteasome activity, a critical pathway by which cells cope with proteotoxic stress. Moreover, we found that treatment with BET inhibitors or depletion of Nrf1 exacerbated the unfolded protein response (UPR), signaling that was initiated by proteasome inhibition. Taken together, our work provides a mechanistic explanation behind the synergy between proteasome and BET inhibitors in cancer cell lines and could prompt future preclinical and clinical studies aimed at further investigating this combination.

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 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 Carfilzomib Promotes the Unfolded Protein Response and Apoptosis in Cetuximab-Resistant Colorectal Cancer

2021 ◽  
Vol 22 (13) ◽  
pp. 7114
Author(s):  
Ahmad Zulkifli ◽  
Fiona H. Tan ◽  
Zammam Areeb ◽  
Sarah F. Stuart ◽  
Juliana Gomez ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Unfolded Protein Response ◽  
Cell Lines ◽  
Intrinsic Resistance ◽  
In Vitro Proliferation ◽  
Unfolded Protein ◽  
Potential Alternative ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Resistant Cells

Cetuximab is a common treatment option for patients with wild-type K-Ras colorectal carcinoma. However, patients often display intrinsic resistance or acquire resistance to cetuximab following treatment. Here we generate two human CRC cells with acquired resistance to cetuximab that are derived from cetuximab-sensitive parental cell lines. These cetuximab-resistant cells display greater in vitro proliferation, colony formation and migration, and in vivo tumour growth compared with their parental counterparts. To evaluate potential alternative therapeutics to cetuximab-acquired-resistant cells, we tested the efficacy of 38 current FDA-approved agents against our cetuximab-acquired-resistant clones. We identified carfilzomib, a selective proteosome inhibitor to be most effective against our cell lines. Carfilzomib displayed potent antiproliferative effects, induced the unfolded protein response as determined by enhanced CHOP expression and ATF6 activity, and enhanced apoptosis as determined by enhanced caspase-3/7 activity. Overall, our results indicate a potentially novel indication for carfilzomib: that of a potential alternative agent to treat cetuximab-resistant colorectal cancer.

scholarly journals Metformin Dysregulates the Unfolded Protein Response and the WNT/β-Catenin Pathway in Endometrial Cancer Cells through an AMPK-Independent Mechanism

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1067
Author(s):  
Domenico Conza ◽  
Paola Mirra ◽  
Gaetano Calì ◽  
Luigi Insabato ◽  
Francesca Fiory ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Unfolded Protein Response ◽  
Cancer Cells ◽  
Independent Manner ◽  
Growth And Survival ◽  
Unfolded Protein ◽  
Compound C ◽  
Survival Pathways ◽  
The Unfolded Protein Response ◽  
Protein Response

Multiple lines of evidence suggest that metformin, an antidiabetic drug, exerts anti-tumorigenic effects in different types of cancer. Metformin has been reported to affect cancer cells’ metabolism and proliferation mainly through the activation of AMP-activated protein kinase (AMPK). Here, we show that metformin inhibits, indeed, endometrial cancer cells’ growth and induces apoptosis. More importantly, we report that metformin affects two important pro-survival pathways, such as the Unfolded Protein Response (UPR), following endoplasmic reticulum stress, and the WNT/β-catenin pathway. GRP78, a key protein in the pro-survival arm of the UPR, was indeed downregulated, while GADD153/CHOP, a transcription factor that mediates the pro-apoptotic response of the UPR, was upregulated at both the mRNA and protein level. Furthermore, metformin dramatically inhibited β-catenin mRNA and protein expression. This was paralleled by a reduction in β-catenin transcriptional activity, since metformin inhibited the activity of a TCF/LEF-luciferase promoter. Intriguingly, compound C, a well-known inhibitor of AMPK, was unable to prevent all these effects, suggesting that metformin might inhibit endometrial cancer cells’ growth and survival through the modulation of specific branches of the UPR and the inhibition of the Wnt/β-catenin pathway in an AMPK-independent manner. Our findings may provide new insights on the mechanisms of action of metformin and refine the use of this drug in the treatment of endometrial cancer.

Sequencing of Argonaute-bound miRNA/mRNA hybrids reveals regulation of the unfolded protein response by microRNA-320a

2021 ◽  
Author(s):  
Christopher J Fields ◽  
Lu Li ◽  
Nicholas M Hiers ◽  
Tianqi Li ◽  
Peike Sheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Cancer Cells ◽  
Rna Polymerase Ii ◽  
Mirna Biogenesis ◽  
Unfolded Protein ◽  
Colorectal Cancer Cells ◽  
The Unfolded Protein Response ◽  
Protein Response

MicroRNAs (miRNA) are short non-coding RNAs widely implicated in gene regulation. Most metazoan miRNAs utilize the RNase III enzymes Drosha and Dicer for biogenesis. One notable exception is the RNA polymerase II transcription start sites (TSS) miRNAs whose biogenesis does not require Drosha. The functional importance of the TSS-miRNA biogenesis is uncertain. To better understand the function of TSS-miRNAs, we applied a modified Crosslinking, Ligation, and Sequencing of Hybrids on Argonaute (AGO-qCLASH) to identify the targets for TSS-miRNAs in HCT116 colorectal cancer cells with or without DROSHA knockout. We observed that miR-320a hybrids dominate in TSS-miRNA hybrids identified by AGO-qCLASH. Targets for miR-320a are enriched in the eIF2 signaling pathway, a downstream component of the unfolded protein response. Consistently, in miR-320a mimic- and antagomir- transfected cells, differentially expressed genes are enriched in eIF2 signaling. Within the AGO-qCLASH data, we identified the endoplasmic reticulum (ER) chaperone Calnexin as a direct miR-320a target, thus connecting miR-320a to the unfolded protein response. During ER stress, but not amino acid deprivation, miR-320a up-regulates ATF4, a critical transcription factor for resolving ER stress. Our study investigates the targetome of the TSS-miRNAs in colorectal cancer cells and establishes miR-320a as a regulator of unfolded protein response.

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 The next generation proteasome inhibitors carfilzomib and oprozomib activate prosurvival autophagy via induction of the unfolded protein response and ATF4

Autophagy ◽  
2012 ◽  
Vol 8 (12) ◽  
pp. 1873-1874 ◽  
Author(s):  
Yan Zang ◽  
Sufi M. Thomas ◽  
Elena T. Chan ◽  
Christopher J. Kirk ◽  
Maria L. Freilino ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Proteasome Inhibitors ◽  
Next Generation ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response
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