scholarly journals Naringin induces endoplasmic reticulum stress-mediated apoptosis, inhibits β-catenin pathway and arrests cell cycle in cervical cancer cells

2020 ◽  
Author(s):  
Shaorong Chen ◽  
Ruyin Lin ◽  
Xinxin Hu ◽  
Qiyang Shi ◽  
Huiqing Chen
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Endoplasmic Reticulum ◽  
Protein Expression ◽  
Er Stress ◽  
Annexin V ◽  
Significant Inhibition ◽  
Cell Cycle Checkpoint ◽  
G1 Phase ◽  
Pre Treatment

Naringin is a promising anticancer bioflavonoid phytochemical, mainly extracted from citrus fruits. This study evaluates the antiproliferative effect and the cell death mechanism induced by naringin on cervical cancer (CC) cells. Our results demonstrated that naringin exerts significant inhibition in cell viability and exhibits IC50 value 745, 764, 793 µM against C33A, SiHa, and HeLa cells respectively. Annexin V FITC and immunoblotting analysis reveal significant apoptosis induction in cells exposed to higher doses naringin. Mechanistically, naringin induces endoplasmic reticulum (ER) stress-associated cell killing in CC cells. Naringin increases the protein expression of ER stress sensors, phosphorylates eIF2α by and activates apoptosis-associated protein CHOP and other associated proapoptotic proteins (PARP1 and caspase-3). Intriguingly, pre-treatment with of ER stress inhibitor (salubrinal), reverses the apoptotic effect exerted by naringin. Additionally, the naringin abrogates the β-catenin pathway by decreasing the protein expression as well as phosphorylation of β-catenin (Ser576) and GSK-3β (Ser9) and simultaneously triggers cell cycle arrest at a G0/G1 phase by increasing the expression of cell cycle checkpoint proteins p21/cip and p27/kip. Naringin induces ER stress-mediated apoptosis and simultaneously abrogates Wnt/β-catenin signaling which eventually triggers the arrest of the cell cycle at a G0/G1 phase in CC cells.

scholarly journals Mitogen-activated Protein Kinase Stimulation of Ca2+Signaling Is Required for Survival of Endoplasmic Reticulum Stress in Yeast

2003 ◽  
Vol 14 (10) ◽  
pp. 4296-4305 ◽  
Author(s):  
Myriam Bonilla ◽  
Kyle W. Cunningham
Keyword(s):  
Cell Cycle ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Protein Kinase ◽  
Er Stress ◽  
Cell Cycle Checkpoint ◽  
Antifungal Drugs ◽  
Mitogen Activated Protein Kinase ◽  
M Cell ◽  
Stimulation Of

Endoplasmic reticulum (ER) stress in the budding yeast Saccharomyces cerevisiae triggers Ca2+influx through a plasma membrane channel composed of Cch1 and Mid1. This response activates calcineurin, which helps to prevent cell death during multiple forms of ER stress, including the response to azole-class antifungal drugs. Herein, we show that ER stress activates the cell integrity mitogen-activate protein kinase cascade in yeast and that the activation of Pkc1 and Mpk1 is necessary for stimulation of the Cch1-Mid1 Ca2+channel independent of many known targets of Mpk1 (Rlm1, Swi4, Swi6, Mih1, Hsl1, and Swe1). ER stress generated in response to miconazole, tunicamycin, or other inhibitors also triggered a transient G2/M arrest that depended upon the Swe1 protein kinase. Calcineurin played little role in the Swe1-dependent cell cycle arrest and Swe1 had little effect on calcineurin-dependent avoidance of cell death. These findings help to clarify the interactions between Mpk1, calcineurin, and Swe1 and suggest that the calcium cell survival pathway promotes drug resistance independent of both the unfolded protein response and the G2/M cell cycle checkpoint.

scholarly journals Cannabidiol Induces Cell Cycle Arrest and Cell Apoptosis in Human Gastric Cancer SGC-7901 Cells

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 302 ◽  
Author(s):  
Xin Zhang ◽  
Yao Qin ◽  
Zhaohai Pan ◽  
Minjing Li ◽  
Xiaona Liu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Cycle ◽  
Protein Expression ◽  
Cell Cycle Arrest ◽  
Phase Cell ◽  
G1 Phase ◽  
Therapeutic Effects ◽  
Human Gastric Cancer ◽  
Expression Levels ◽  
Cycle Arrest

The main chemical component of cannabis, cannabidiol (CBD), has been shown to have antitumor properties. The present study examined the in vitro effects of CBD on human gastric cancer SGC-7901 cells. We found that CBD significantly inhibited the proliferation and colony formation of SGC-7901 cells. Further investigation showed that CBD significantly upregulated ataxia telangiectasia-mutated gene (ATM) and p53 protein expression and downregulated p21 protein expression in SGC-7901 cells, which subsequently inhibited the levels of CDK2 and cyclin E, thereby resulting in cell cycle arrest at the G0–G1 phase. In addition, CBD significantly increased Bax expression levels, decreased Bcl-2 expression levels and mitochondrial membrane potential, and then upregulated the levels of cleaved caspase-3 and cleaved caspase-9, thereby inducing apoptosis in SGC-7901 cells. Finally, we found that intracellular reactive oxygen species (ROS) increased after CBD treatment. These results indicated that CBD could induce G0–G1 phase cell cycle arrest and apoptosis by increasing ROS production, leading to the inhibition of SGC-7901 cell proliferation, thereby suggesting that CBD may have therapeutic effects on gastric cancer.

scholarly journals Chemosensitization of HT29 and HT29-5FU Cell Lines by a Combination of a Multi-Tyrosine Kinase Inhibitor and 5FU Downregulates ABCC1 and Inhibits PIK3CA in Light of Their Importance in Saudi Colorectal Cancer

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 334
Author(s):  
Ashraf N. Abdalla ◽  
Waleed H. Malki ◽  
Amal Qattan ◽  
Imran Shahid ◽  
Mohammad Akbar Hossain ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Abc Transporters ◽  
Kinase Inhibitor ◽  
Annexin V ◽  
Significant Inhibition ◽  
Pik3ca Mutations ◽  
Reversal Effect ◽  
Development Of Resistance

Colorectal cancer (CRC) remains one of the main causes of death worldwide and in Saudi Arabia. The toxicity and the development of resistance against 5 fluorouracil 5FU pose increasing therapeutic difficulties, which necessitates the development of personalized drugs and drug combinations. Objectives: First, to determine the most important kinases and kinase pathways, and the amount of ABC transporters and KRAS in samples taken from Saudi CRC patients. Second, to investigate the chemosensitizing effect of LY294002 and HAA2020 and their combinations with 5FU on HT29, HT29-5FU, HCT116, and HCT116-5FU CRC cells, their effect on the three ABC transporters, cell cycle, and apoptosis, in light of the important kinase pathways resulting from the first part of this study. Methods: The PamChip® peptide micro-array profiling was used to determine the level of kinase and targets in the Saudi CRC samples. Next, RT-PCR, MTT cytotoxicity, Western blotting, perturbation of cell cycle, annexin V, and immunofluorescence assays were used to investigate the effect on CRC, MRC5, and HUVEC cells. Results: The kinase activity profiling highlighted the importance of the PI3K/AKT, MAPK, and the growth factors pathways in the Saudi CRC samples. PIK3CA was the most overexpressed, and it was associated with increased level of mutated KRAS and the three ABC transporters, especially ABCC1 in the Saudi samples. Next, combining HAA2020 with 5FU exhibited the best synergistic and resistance-reversal effect in the four CRC cells, and the highest selectivity indices compared to MRC5 and HUVEC normal cells. Additionally, HAA2020 with 5FU exerted significant inhibition of ABCC1 in the four CRC cells, and inhibition of PIK3CA/AKT/MAPK7/ERK in HT29 and HT29-5FU cells. The combination also inhibited EGFR, increased the preG1/S cell cycle phases, apoptosis, and caspase 8 in HT29 cells, while it increased the G1 phase, p21/p27, and apoptosis in HT29-5FU cells. Conclusion: We have combined the PamChip kinase profiling of Saudi CRC samples with in vitro drug combination studies in four CRC cells, highlighting the importance of targeting PIK3CA and ABCC1 for Saudi CRC patients, especially given that the overexpression of PIK3CA mutations was previously linked with the lack of activity for the anti-EGFRs as first line treatment for CRC patients. The combination of HAA2020 and 5FU has selectively sensitized the four CRC cells to 5FU and could be further studied.

scholarly journals Aromadendrin Protects Neuronal Cells from Methamphetamine-Induced Neurotoxicity by Regulating Endoplasmic Reticulum Stress and PI3K/Akt/mTOR Signaling Pathway

2021 ◽  
Vol 22 (5) ◽  
pp. 2274
Author(s):  
Hyun-Su Lee ◽  
Eun-Nam Kim ◽  
Gil-Saeng Jeong
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Signaling Pathway ◽  
Neuronal Cells ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Irreversible Damage ◽  
Pre Treatment ◽  
Apoptotic Pathways

Methamphetamine (METH) is a highly addictive drug that induces irreversible damage to neuronal cells and pathological malfunction in the brain. Aromadendrin, isolated from the flowers of Chionanthus retusus, has been shown to have anti-inflammatory or anti-tumor activity. Nevertheless, it has been reported that METH exacerbates neurotoxicity by inducing endoplasmic reticulum (ER) stress via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway in neuronal cells. There is little evidence that aromadendrin protects cells from neurotoxicity induced by METH. In this study, we found that aromadendrin partially suppressed the METH-induced cell death in SH-SY5y cells without causing cytotoxicity. Aromadendrin regulated METH-induced ER stress by preserving the phosphorylation of the PI3K/Akt/mTOR signaling pathway in METH-exposed SH-SY5y cells. In addition, aromadendrin mitigated METH-induced autophagic and the apoptotic pathways in METH-exposed SH-SY5y cells. Mechanistic studies revealed that pre-treatment with aromadendrin restored the expression of anti-apoptotic proteins in METH-exposed conditions. The inhibitor assay confirmed that aromadendrin-mediated restoration of mTOR phosphorylation protected cells from autophagy and apoptosis in METH-exposed cells. Therefore, these findings suggest that aromadendrin relatively has a protective effect on SH-SY5y cells against autophagy and apoptosis induced by METH via regulation of ER stress and the PI3K/Akt/mTOR signaling pathway.

Apigetrin Promotes Cell Autophagy by Activating the Endoplasmic Reticulum Stress in Human Cervical Cancer Hela Cells

2021 ◽  
Vol 20 (1) ◽  
pp. 56-63
Author(s):  
Li Jiang ◽  
Zhi-Cheng Yao ◽  
Miao-Miao Liu ◽  
Run-Hui Ma ◽  
Kiran Thakur
Keyword(s):  
Cervical Cancer ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Hela Cells ◽  
Fruits And Vegetables ◽  
Radical Scavenging ◽  
Anticancer Activities ◽  
Treatment Results ◽  
Metastasis Rate ◽  
The Relationship

Cervical cancer has always been the top malignant cancer among female cancers in the world. Due to its recurrence, metastasis rate, and drug resistance, the treatment results of cervical cancer have been unsatisfactory. Apigetrin is present in a variety of fruits and vegetables and has been reported to have antioxidant, free radical scavenging, anti-inflammatory, and anticancer activities. Therefore, this study focuses on the effect of apigetrin on the autophagy of cervical cancer HeLa cells based on the previous research. The results showed that apigetrin can enhance the autophagy fluorescence of light chain 3B (LC3B), and further combined with quantitative real-time PCR (qPCR) and Western blotting found that the expression of autophagy-related genes and proteins p-mTOR, Beclin1, and LC3B increased, while the expression of AMPK, ULK1, and p62 decreased. In addition, apigetrin also promoted the release of Ca2+, the PERK/eIF2α/ATF4/chop, and IRE1α pathways activate endoplasmic reticulum (ER) stress. The addition of 4PBA proved that ER stress promoted autophagy in HeLa cells. Finally, the addition of the 3-MA indicates the relationship between autophagy and apoptosis in HeLa cells. Our results indicate that apigetrin has a certain anticancer potential and can be used as a drug adjuvant and food additive for the prevention and treatment of cervical cancer.

scholarly journals RHBDL4 protects against endoplasmic reticulum stress by regulating the morphology and distribution of ER sheets

2021 ◽  
Author(s):  
Viorica Liebe Lastun ◽  
Matthew Freeman
Keyword(s):  
Cell Cycle ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Liver Steatosis ◽  
Physiological Role ◽  
Cell Types ◽  
Rhomboid Protease ◽  
Rapid Changes

In metazoans, the architecture of the endoplasmic reticulum (ER) differs between cell types, and undergoes major changes through the cell cycle and according to physiological needs. Although much is known about how the different ER morphologies are generated and maintained, especially the ER tubules, how context dependent changes in ER shape and distribution are regulated and the factors involved are less characterized. Here, we show that RHBDL4, an ER-resident rhomboid protease, modulates the shape and distribution of the ER, especially under conditions that require rapid changes in the ER sheet distribution, including ER stress. RHBDL4 interacts with CLIMP-63, a protein involved in ER sheet stabilisation, and with the cytoskeleton. Mice lacking RHBDL4 are sensitive to ER stress and develop liver steatosis, a phenotype associated with unresolved ER stress. Our data introduce a new physiological role of RHBDL4 and also imply that this function does not require its enzymatic activity.

scholarly journals Total Phenols, Identification of Active Compounds and Anticancer Activity of Salvia judaica Boiss against the breast Cancer Cell MDA-231

2021 ◽  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Essential Oil ◽  
Anticancer Activity ◽  
Breast Cancer Cell ◽  
Annexin V ◽  
Ethanol Extract ◽  
G1 Phase ◽  
Apoptotic Cells ◽  
Total Phenols

Salvia judaica is an annual herb from genus Salvia L.; the largest genera of Lamiaceae. It’s a medicinal plant prominent in pharmaceutical applications in many countries around the world. This study aimed to explore bioactive compounds likely to be responsible for the plant anticancer activity, and evaluate anticancer effects, after determining the total content of phenols in the ethanol extract and essential oil in this species. Ethanol extract (EE) and essential oil (EO) were prepared from dried aerial parts (leaves and the flower). GC-MS analysis of EO showed the presence of/43/ effective compounds in varying proportions, the major compounds were sesquiterpenes like delta-cadinene, alpha-Gurjunene, beta-humulene, and alpha-caryophyllene. This is the first study revealed that S.judaica is so rich in phenols which proceeded S.officinalis, noting the superiority of the EE over the EO samples in the total phenols. Anticancer properties of EE and EO of S. judaica against MDA-231 breast cancer cell line were studied -for the first time - by cell cycle analysis and Annexin V/PI apoptosis assay using Flow cytometry technique. Cells were treated with EE (0.001, 0.01, 0.02, 0.1mg/ml) and EO (0.005, 0.01, 0.02, 0.03, 0.04 mg/ml) at various concentrations for48 h. The results revealed that both EE and EO induced cell cycle arrest at G1-phase. Cells treated with EE and EO for 48h showed increasing the percentage of cells in G1-phase and decreasing the percentage of cells in S-phase with increasing concentration compared with untreated cells (control). Annexin V-FITC/PI assay confirmed that EO and EE were able to induce apoptosis. Cells treated with EOat (0.04 mg/ml) for 48h resulted in apoptotic cells at 96.68%, and necrotic cells at 0.12%, compared with untreated cells. On the other hand, Cells treated with EE at (0.1 mg/ml) for 48h resulted in apoptotic cells at 94.43%, and necrotic cells at 0.47%, compared with control. Results revealed that EO is better than EE as anticancer; treatment with EO resulted in more apoptotic cells and less necrotic cells, and there were significant differences between them. This confirmed that EO contains specific anticancer compounds as showed by GC-MS analysis. However, more studies should be performed to explore antioxidants present in S.judaica and determine the underlying mechanism of their anti-breast cancer properties.

scholarly journals The ER Stress Surveillance (ERSU) pathway regulates daughter cell ER protein aggregate inheritance

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Francisco J Piña ◽  
Maho Niwa
Keyword(s):  
Cell Cycle ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Mother Cell ◽  
Daughter Cell ◽  
Protein Aggregates ◽  
Cytoplasmic Protein ◽  
Protein Aggregate ◽  
Daughter Cells ◽  
Simultaneous Visualization

Stress induced by cytoplasmic protein aggregates can have deleterious consequences for the cell, contributing to neurodegeneration and other diseases. Protein aggregates are also formed within the endoplasmic reticulum (ER), although the fate of ER protein aggregates, specifically during cell division, is not well understood. By simultaneous visualization of both the ER itself and ER protein aggregates, we found that ER protein aggregates that induce ER stress are retained in the mother cell by activation of the ER Stress Surveillance (ERSU) pathway, which prevents inheritance of stressed ER. In contrast, under conditions of normal ER inheritance, ER protein aggregates can enter the daughter cell. Thus, whereas cytoplasmic protein aggregates are retained in the mother cell to protect the functional capacity of daughter cells, the fate of ER protein aggregates is determined by whether or not they activate the ERSU pathway to impede transmission of the cortical ER during the cell cycle.

Overexpressed miR-375-Loaded Restrains Development of Cervical Cancer Through Down-Regulation of Frizzled Class Receptor 4 (FZD4) with Liposome Nanoparticle as a Carrier

2021 ◽  
Vol 17 (9) ◽  
pp. 1882-1889
Author(s):  
Suqin Wang ◽  
Lina Xu ◽  
Zhiqiang Zhang ◽  
Ping Wang ◽  
Rong Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Cell Proliferation ◽  
Protein Expression ◽  
Signaling Pathway ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Gene Assay ◽  
M Phase ◽  
The Impact

Dysregulation expression of miR-375 is noted to correlate with progression of cervical cancer. This study attempted to investigate the impact of overexpressed miR-375-loaded liposome nanoparticles on proliferation of cervical cancer (CC), to provide an insight on pathogenesis of CC disorder. CC cells were co-cultured with pure liposome nanoparticles (empty vector group), miR-375 agonist-loaded liposome nanoparticles, or transfected with miR-375 antagonist. Besides, some cells were exposed to TGF-β/Smads signaling pathway inhibitor or activator whilst cell proliferation was assessed by MTT assay, and expressions of FZD4 and miR-375 were determined. Western blot analysis was carried out to detect the expression of TGF-β pathway factors (TGF-β, Smad2, Smad7, p-Smad2) and its downstream Smads pathway. The interaction between miR-375 and FZD4 was evaluated by dual-luciferase reporter gene assay. Overexpression of miR-375 induced arrest at the G0/G1 phase of cell cycle and elevation of Smad2 protein expression (P <0.05), with lower expressions of TGF-β, Smad7, p-Smad2, and FZD4, while transfection with miR-375 inhibitor exhibited opposite activity. Presence of miR-375 agonist-loaded liposome nanoparticles induced decreased cell proliferation. There was a targeting relationship between miR-375 and FZD4, and administration with TGF-β/Smads agonist resulted in increased miR-375 and Smad2 expressions, as well as decreased TGF-β, Smad7, p-Smad2, FZD4 protein expression, and the number of S phase and G2/M phase cells (P < 0.05). The signaling inhibitor oppositely suppressed cell proliferation decreasing miR-375 expression. miR-375-loaded liposome nanoparticles activated TGF-β/Smads signaling pathway to restrain cell cycle and suppress cell division, and proliferation through targeting FZD4 in CC. Its molecular mechanism is related to activation of TGF-β/Smads signaling pathway.

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