scholarly journals Retrochalcone Echinatin Triggers Apoptosis of Esophageal Squamous Cell Carcinoma via ROS- and ER Stress-Mediated Signaling Pathways

Molecules ◽  
2019 ◽  
Vol 24 (22) ◽  
pp. 4055 ◽  
Author(s):  
Ah-Won Kwak ◽  
Joon-Seok Choi ◽  
Mee-Hyun Lee ◽  
Ha-Na Oh ◽  
Seung-Sik Cho ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Er Stress ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Stress Proteins ◽  
Cyclin B1 ◽  
Stress Generation ◽  
Protein Markers ◽  
Stress Dependent

Esophageal squamous cell carcinoma (ESCC) is a poor prognostic cancer with a low five-year survival rate. Echinatin (Ech) is a retrochalone from licorice. It has been used as a herbal medicine due to its anti-inflammatory and anti-oxidative effects. However, its anticancer activity or underlying mechanism has not been elucidated yet. Thus, the objective of this study was to investigate the anti-tumor activity of Ech on ESCC by inducing ROS and ER stress dependent apoptosis. Ech inhibited ESCC cell growth in anchorage-dependent and independent analysis. Treatment with Ech induced G2/M phase of cell cycle and apoptosis of ESCC cells. It also regulated their related protein markers including p21, p27, cyclin B1, and cdc2. Ech also led to phosphorylation of JNK and p38. Regarding ROS and ER stress formation associated with apoptosis, we found that Ech increased ROS production, whereas its increase was diminished by NAC treatment. In addition, ER stress proteins were induced by treatment with Ech. Moreover, Ech enhanced MMP dysfunction and caspases activity. Furthermore, it regulated related biomarkers. Taken together, our results suggest that Ech can induce apoptosis in human ESCC cells via ROS/ER stress generation and p38 MAPK/JNK activation.

scholarly journals Podophyllotoxin Isolated from Podophyllum peltatum Induces G2/M Phase Arrest and Mitochondrial-Mediated Apoptosis in Esophageal Squamous Cell Carcinoma Cells

Forests ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 8 ◽  
Author(s):  
Goo Yoon ◽  
Mee-Hyun Lee ◽  
Ah-Won Kwak ◽  
Ha-Na Oh ◽  
Seung-Sik Cho ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Er Stress ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Podophyllum Peltatum ◽  
Phase Arrest ◽  
Anti Cancer ◽  
M Phase ◽  
Stress Dependent

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in East Asia and is the seventh leading cause of cancer deaths. Podophyllotoxin (PT), a cyclolignan isolated from podophyllum peltatum, exhibits anti-cancer effects at the cellular level. This study investigated the underlying mechanism of anti-cancer effects induced by PT in ESCC cells. Exposure to increasing concentrations of PT led to a significant decrease in the growth and anchorage-independent colony numbers of ESCC cells. PT showed high anticancer efficacy against a panel of four types of ESCC cells, including KYSE 30, KYSE 70, KYSE 410, KYSE 450, and KYSE 510 by IC50 at values ranges from 0.17 to 0.3 μM. We also found that PT treatment induced G2/M phase arrest in the cell cycle and accumulation of the sub-G1 population, as well as apoptosis. Exposure to PT triggered a significant synthesis of reactive oxygen species (ROS), a loss of mitochondrial membrane potential (MMP), and activation of various caspases. Furthermore, PT increased the levels of phosphorylated c-Jun N-terminal kinase (JNK), p38, and the expression of Endoplasmic reticulum (ER) stress marker proteins via ROS generation. An increase in the level of pro-apoptotic proteins and a reduction in the anti-apoptotic protein level induced ESCC cell death via the loss of MMP. Additionally, the release of cytochrome c into the cytosol with Apaf-1 induced the activation of multi-caspases. In conclusion, our results revealed that PT resulted in apoptosis of ESCC cells by modulating ROS-mediated mitochondrial and ER stress-dependent mechanisms. Therefore, PT is a promising therapeutic candidate as an anti-cancer drug against ESCC for clinical use.

scholarly journals Deoxypodophyllotoxin, a Lignan from Anthriscus sylvestris, Induces Apoptosis and Cell Cycle Arrest by Inhibiting the EGFR Signaling Pathways in Esophageal Squamous Cell Carcinoma Cells

2020 ◽  
Vol 21 (18) ◽  
pp. 6854
Author(s):  
Ah-Won Kwak ◽  
Mee-Hyun Lee ◽  
Goo Yoon ◽  
Seung-Sik Cho ◽  
Joon-Seok Choi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Reactive Oxygen Species Generation ◽  
Direct Interaction ◽  
Cyclin B1 ◽  
Dependent Manner ◽  
Anthriscus Sylvestris

Deoxypodophyllotoxin (DPT) derived from Anthriscus sylvestris (L.) Hoffm has attracted considerable interest in recent years because of its anti-inflammatory, antitumor, and antiviral activity. However, the mechanisms underlying DPT mediated antitumor activity have yet to be fully elucidated in esophageal squamous cell carcinoma (ESCC). We show here that DPT inhibited the kinase activity of epidermal growth factor receptor (EGFR) directly, as well as phosphorylation of its downstream signaling kinases, AKT, GSK-3β, and ERK. We confirmed a direct interaction between DPT and EGFR by pull-down assay using DPT-beads. DPT treatment suppressed ESCC cell viability and colony formation in a time- and dose-dependent manner, as shown by MTT analysis and soft agar assay. DPT also down-regulated cyclin B1 and cdc2 expression to induce G2/M phase arrest of the cell cycle and upregulated p21 and p27 expression. DPT treatment of ESCC cells triggered the release of cytochrome c via loss of mitochondrial membrane potential, thereby inducing apoptosis by upregulation of related proteins. In addition, treatment of KYSE 30 and KYSE 450 cells with DPT increased endoplasmic reticulum stress, reactive oxygen species generation, and multi-caspase activation. Consequently, our results suggest that DPT has the potential to become a new anticancer therapeutic by inhibiting EGFR mediated AKT/ERK signaling pathway in ESCC.

scholarly journals Apatinib induces endoplasmic reticulum stress-mediated apoptosis and autophagy and potentiates cell sensitivity to paclitaxel via the IRE-1α–AKT–mTOR pathway in esophageal squamous cell carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yu-Ming Wang ◽  
Xin Xu ◽  
Jian Tang ◽  
Zhi-Yong Sun ◽  
Yu-Jie Fu ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Endoplasmic Reticulum ◽  
Esophageal Squamous Cell Carcinoma ◽  
Er Stress ◽  
Cell Carcinoma ◽  
Cancer Cells ◽  
Squamous Cell ◽  
Molecular Mechanisms ◽  
Mtor Pathway ◽  
Induced Apoptosis

Abstract Background Apatinib, a novel vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, has been approved for the treatment of metastatic gastric cancer and other tumors. Apatinib exerts antiproliferative and proapoptotic effects in different kinds of cancer cells. However, the molecular mechanisms by which apatinib effective against esophageal squamous cell carcinoma (ESCC) have only been partially researched and whether it has a sensitizing effect on paclitaxel remains unclear. Materials and methods The effects of apatinib or paclitaxel on endoplasmic reticulum (ER) stress, autophagy, apoptosis and proliferation of ESCC cell lines were evaluated. Western blot and immunohistochemistry analyses were performed to detect the expression of related genes. The weight and volume of xenograft tumors in mice were measured. Results In the current study, we elucidated the antiproliferative and ER-stress-mediated autophagy-inducing effects of apatinib on ECA-109 and KYSE-150 esophageal squamous cancer cells and identified the underlying mechanisms of its action. We demonstrated that apatinib not only inhibited the proliferation and induced the apoptosis of ESCC cells, but also activated ER stress and triggered protective autophagy. Moreover, inhibiting autophagy by chloroquine (CQ) enhanced the apatinib-induced apoptosis of ESCC cells through the IRE-1α–AKT–mTOR pathway. In addition, we showed, for the first time, the paclitaxel combined with apatinib and CQ exhibited the best antitumor effect on ESCC both in vivo and in vitro via the IRE-1α–AKT–mTOR pathway. Conclusions Our data showed that apatinib induced ER stress, autophagy and apoptosis in ESCC. Inhibiting autophagy by CQ enhanced apatinib-induced apoptosis. The combination of apatinib and CQ sensitized ESCC cells to paclitaxel to induce apoptosis through the IRE-1α–AKT–mTOR signaling pathway, thus providing the basis for its use in innovative anticancer therapeutic strategies. Graphic abstract

Prognostic value of cyclin B1 in patients with esophageal squamous cell carcinoma

Cancer ◽  
2002 ◽  
Vol 94 (11) ◽  
pp. 2874-2881 ◽  
Author(s):  
Shinsuke Takeno ◽  
Tsuyoshi Noguchi ◽  
Ryuichi Kikuchi ◽  
Yuzo Uchida ◽  
Shigeo Yokoyama ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Prognostic Value ◽  
Cyclin B1
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