scholarly journals CAAT/Enhancer Binding Protein Homologous Protein–Dependent Death Receptor 5 Induction Is a Major Component of SHetA2-Induced Apoptosis in Lung Cancer Cells

2008 ◽  
Vol 68 (13) ◽  
pp. 5335-5344 ◽  
Author(s):  
Yi-Dan Lin ◽  
Shuzhen Chen ◽  
Ping Yue ◽  
Wei Zou ◽  
Doris M. Benbrook ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Binding Protein ◽  
Death Receptor ◽  
Lung Cancer Cells ◽  
Death Receptor 5 ◽  
Homologous Protein ◽  
Enhancer Binding Protein ◽  
Induced Apoptosis

scholarly journals A Small Molecule Inhibitor of Deubiquitinase OTUD3 Promotes DR5-Induced Apoptosis in Lung Cancer Through ER Stress Modulation

2021 ◽  
Author(s):  
Tongde Du ◽  
Juan Wang ◽  
Ya Lu ◽  
Chenxin Xu ◽  
Jianzhong Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Er Stress ◽  
Cancer Cells ◽  
Death Receptor ◽  
Cancer Prognosis ◽  
Lung Cancer Cells ◽  
Cell Surface Expression ◽  
Death Receptor 5 ◽  
Induced Apoptosis

Abstract Background: Lung cancer is cancer with the highest morbidity and mortality in the world and poses a serious threat to human health. Therefore, discovering new treatments is urgently needed to improve lung cancer prognosis. The ubiquitin-proteasome system is an important target for the research of antineoplastic drugs, in which deubiquitinase inhibitors have broad clinical applications. In this study, we show that Rolapitant, an inhibitor of deubiquitinase OTUD3, can inhibit the proliferation and induce apoptosis of lung cancer cells through OTUD3. Methods: Cell viability was measured by CCK8 assays. Apoptosis, cell cycle and surface DR5 expression on lung cancer cells were analyzed by flow cytometry. The expression of transcription level was measured by real time RT-PCR methods. Protein expression was examined in Rolapitant-treated lung cancer cells using Western blotting. Proteomics sequencing was used to detect the molecules which Rolapitant regulate. A549 xenograft nude mice were used to assess the efficacy of Rolapitant in vivo.Result: We showed that Rolapitant enhanced the ubiquitination levels of substrate GRP78 and reduced its protein level. Proteomics sequencing indicated that Rolapitant significantly upregulated the expression of death receptor 5 (DR5). Rolapitant also promoted lung cancer cell apoptosis through upregulating cell surface expression of DR5 and enhanced TRAIL-induced apoptosis. Mechanistically, Rolapitant directly targeted the OTUD3-GRP78 axis to trigger endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP)-DR5 signaling, sensitizing lung cancer cells to TRAIL-induced apoptosis. In the vivo assays, Rolapitant suppressed the growth of lung cancer xenografts in immunocompromised mice at suitable dosages without apparent toxicity.Conclusions: Therefore, the present study identifies Rolapitant as a novel inhibitor of deubiquitinase OTUD3 and establishes that the OTUD3-GRP78 axis is a potential therapeutic target for lung cancer.

scholarly journals Ciprofloxacin Enhances TRAIL-Induced Apoptosis in Lung Cancer Cells by Upregulating the Expression and Protein Stability of Death Receptors through CHOP Expression

2018 ◽  
Vol 19 (10) ◽  
pp. 3187 ◽  
Author(s):  
Eun Lim ◽  
Yu Yoon ◽  
Jeonghoon Heo ◽  
Tae Lee ◽  
Young-Ho Kim
Keyword(s):  
Lung Cancer ◽  
Protein Stability ◽  
Cancer Cells ◽  
Death Receptor ◽  
Proteolytic Processing ◽  
Receptor Expression ◽  
Host Cells ◽  
Lung Cancer Cells ◽  
Regulation Of Transcription ◽  
Induced Apoptosis

Ciprofloxacin (CIP) is a potent antimicrobial agent with multiple effects on host cells and tissues. Previous studies have highlighted their proapoptotic effect on human cancer cells. The current study showed that subtoxic doses of CIP effectively sensitized multiple cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Although TRAIL alone mediated the partial proteolytic processing of procaspase-3 in lung cancer cells, co-treatment with CIP and TRAIL efficiently restored the complete activation of caspases. We found that treatment of lung cancer with CIP significantly upregulated the expression and protein stability of death receptor (DR) 5. These effects were mediated through the regulation of transcription factor CCAT enhancer-binding protein homologous protein (CHOP) since the silencing of these signaling molecules abrogated the effect of CIP. Taken together, these results indicated that the upregulation of death receptor expression and protein stability by CIP contributed to the restoration of TRAIL-sensitivity in lung cancer cells.

scholarly journals p53-Mediated Oxidative Stress Enhances Indirubin-3′-Monoxime-induced Apoptosis in HCT116 Colon Cancer Cells by Upregulating Death Receptor 5 and TNF-related Apoptosis-inducing Ligand Expression

2019 ◽  
Author(s):  
Matharage Gayani Dilshara ◽  
Ilandarage Menu Neelaka Molagoda ◽  
Rajapaksha Gedara Prasad Tharanga Jayasooriya ◽  
Yung Hyun Choi ◽  
Cheol Park ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Death Receptor ◽  
Chimeric Antibody ◽  
Ros Production ◽  
Death Receptor 5 ◽  
Homologous Protein ◽  
Anti Cancer ◽  
Ligand Expression ◽  
Induced Apoptosis ◽  
Factor C

Indirubin-3′-monoxime (I3M) exhibits anti-proliferative activity in various cancer cells; however, its anti-cancer mechanism remains incompletely elucidated. This study revealed that I3M promotes the expression of death receptor 5 (DR5) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in HCT116 p53+/+ cells, resulting in caspase-mediated apoptosis. However, this study demonstrated that HCT116 p53-/- cells are insensitive to I3M-mediated apoptosis, indicating that I3M-induced apoptosis depends on the p53 status of HCT116 cells. Additionally, in HCT116 p53-/- cells, I3M significantly increased Ras expression, while in HCT116 p53+/+ cells, it reduced Ras expression. Furthermore, I3M remarkably increased the production of reactive oxygen species (ROS), which were reduced in transient p53 knockdown, indicating that I3M-mediated apoptosis is promoted by p53-mediated ROS production. Our results also showed that I3M enhanced transcription factor C/EBP homologous protein (CHOP) expression, resulting in endoplasmic reticulum (ER) stress-mediated DR5 expression, which is upregulated by ROS production in HCT116 p53+/+ cells. Moreover, co-treatment with TRAIL synergistically enhanced I3M-induced DR5 expression, thereby triggering TRAIL-induced apoptosis of HCT116 p53+/+ cells, which was interfered by a DR5-specific blocking chimeric antibody. In summary, I3M potently enhances TRAIL-induced apoptosis by upregulating DR5 expression via p53-mediated ROS production in HCT116 p53+/+ cells. However, HCT116 p53-/- cells were resistant to I3M-mediated apoptosis, suggesting that I3M could be a promising anti-cancer candidate against TRAIL-resistant p53+/+ cancer cells.

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