scholarly journals Atiprimod Triggered Apoptotic Cell Death via Acting on PERK/eIF2a/ATF4/CHOP and STAT3/NF-KB axis in MDA-MB-231 and MDA-MB-468 Breast Cancer Cells

2021 ◽  
Author(s):  
Ajda Coker-Gurkan ◽  
Esin Can ◽  
Semanur Sahin ◽  
PINAR OBAKAN YERLIKAYA ◽  
Elif-Damla ARISAN
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Er Stress ◽  
Cancer Cells ◽  
Tyrosine Kinases ◽  
Breast Cancer Cells ◽  
Apoptotic Cell ◽  
Pivotal Role ◽  
Type I ◽  
Stat3 Phosphorylation

Abstract Purpose: The constitutive activation of STAT3 through receptor tyrosine kinases triggered breast cancer cell growth, and invasion-metastasis. Atiprimod impacts anti-proliferative, anti-carcinogenic effects in hepatocellular carcinoma, lymphoma, multiple myeloma via hindering the biological activity of STAT3. Dose-dependent atiprimod evokes first autophagy as a survival mechanism and then apoptosis due to prolonged ER stress in pituitary adenoma cells. The therapeutic efficiency and mechanistic action of atiprimod in breast cancer cells have not been investigated yet. Thus, we aimed to modulate the pivotal role of ER stress in atiprimod-triggered apoptosis in MDA-MB-231 and MDA-MB-468 breast cancer cells. Results: Dose- and time-dependent atiprimod treatment inhibits cell viability and colony formation in MDA-MB-468 and MDA-MB-231 breast cancer cells. A moderate dose of atiprimod (2 mM) inhibited STAT3 phosphorylation at Tyr705 residue and also suppressed the total expression level of p65. In addition, nuclear localization of STAT1, 3 and NF-kB was prevented by atiprimod exposure in MDA-MB-231 and MDA-MB-468 cells. Atiprimod evokes PERK, BiP, ATF-4, CHOP upregulation, and PERK (Thr980), eIF2a (Ser51) phosphorylation’s. However, atiprimod suppressed IRE1a-mediated Atg-3, 5, 7, 12 protein expressions and no alteration were observed on Beclin-1, p62 expression levels. PERK/eIF2a/ATF4/CHOP axis pivotal role in atiprimod-mediated G1/S arrest and apoptosis via Bak, Bax, Bim and PUMA upregulation in MDA-MB-468 cells. Moreover, atiprimod renders MDA-MB-231 more vulnerable to type I programmed cell death by plasmid-mediated increased STAT3 expression. Conclusion: Atiprimod induced prolonged ER stress-mediated apoptosis via both activating PERK/eIF2a/ATF4/CHOP axis and suppressing STAT3/NF-kB transcription factors nuclear migration in TBNC cells.

scholarly journals Autocrine Growth Hormone (GH)-Mediated Triptolide Resistance Overcame by Metformin Co-Treatment in MDA-MB231 Breast Cancer Cells Through ER Stress Pathway

Proceedings ◽  
2019 ◽  
Vol 40 (1) ◽  
pp. 9
Author(s):  
Amani Abdulmunem ◽  
Pınar Obakan-Yerlikaya ◽  
Elif-Damla Arisan ◽  
Ajda Coker-Gurkan
Keyword(s):  
Breast Cancer ◽  
Growth Hormone ◽  
Cell Death ◽  
Er Stress ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Autocrine Growth ◽  
Common Cancer

Breast cancer is the most common cancer in women worldwide and the second most common cancer overall. Autocrine growth hormone (GH) expression induced cell proliferation, growth, invasion-metastasis in vitro and in vivo breast cancer models. Moreover, forced GH signaling acts as a drug resistance profile in breast cancer cell lines against chemotherapeutic drugs such as tamoxifen, mitomycin C, doxorubicin and curcumin. Triptolide, an active plant extract from Tripterygium wilfordii, has been shown to induce apoptotic cell death in various cancer cells such a prostate, colon, breast cancer. Metformin, a common therapeutic agent for type II Diabetes mellitus, has been shown to induce autophagy, endoplasmic reticulum (ER) stress and apoptotic cell death in cancer cells. Our aim is to demonstrate the potential effect of metformin on triptolide-mediated drug resistance in autocrine GH expressing MDA-MB-231 breast cancer cells through Endoplasmic reticulum (ER) stress. Autocrine GH-mediated triptolide (20 nM) resistance overcame by metformin (2 mM) co-teatment in MDA-MB231 breast cancer cells through accelerating cell viability loss, growth inhibition compared to alone triptolide treatment. Combined treatment increased apoptotic cell death via CHOP activation, IRE1α upregulation. Consequently, we suggest that triptolide can be more effective with metformin combination in MDA-MB-231 GH+ drug resistant breast cancer cells.

Sulindac induces apoptotic cell death in susceptible human breast cancer cells through, at least in part, inhibition of IKKβ

APOPTOSIS ◽  
2009 ◽  
Vol 14 (7) ◽  
pp. 913-922 ◽  
Author(s):  
A-Mi Seo ◽  
Seung-Woo Hong ◽  
Jae-Sik Shin ◽  
In-Chul Park ◽  
Nam-Joo Hong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Human Breast Cancer Cells ◽  
Human Breast

scholarly journals Cordyceps militaris Induces Immunogenic Cell Death and Enhances Antitumor Immunogenic Response in Breast Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Xingguo Quan ◽  
Beom Seok Kwak ◽  
Ji-Young Lee ◽  
Jin Hee Park ◽  
Anbok Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Checkpoint Inhibitors ◽  
Apoptotic Cell ◽  
Annexin V ◽  
Cfse Dilution ◽  
Mouse Breast Cancer ◽  
Treated Breast

Cordyceps militaris has been widely used as a traditional medicine in East Asia. Its effects against breast cancer have been reported previously. However, whether C. militaris-induced breast cancer cell death is immunogenic remains unelucidated. This study aimed to determine whether ethanolic extracts of C. militaris (CM-EE) could induce immunogenic cell death (ICD) in breast cancer immunotherapy to improve the efficacy of immune checkpoint inhibitors. Human and mouse breast cancer cells were treated with various concentrations of CM-EE for 72 h, and cytotoxicity was measured using the sulforhodamine B assay. Flow cytometry was used to assess cell death with annexin V/7-AAD staining and measure the surface exposure of damage-associated molecular pattern (DAMP) molecules including calreticulin, HSP70, and HSP90. Western blot for cleaved poly (ADP-ribose) polymerase (PARP) was used to confirm apoptotic cell death. The immunogenicity of CM-EE-induced dead cells was evaluated using the CFSE dilution assay. CM-EE reduced the viability of human (MCF7, MDA-MB-231, HS578T, and SKBR3) and mouse (4T1-neu-HA, TUBO-HA, and TUBO-P2J-HA) breast cancer cells. The IC50 was 25–50 µg/ml in human breast cancer cells and 10–50 µg/ml in mouse breast cancer cells at 72 h. CM-EE-treated breast cancer cells were positively stained by annexin V, cleaved PARP, and cleaved caspase 3/7 which were increased upon CM-EE treatment. Surface exposure of DAMP molecules was increased in dose- and time-dependent manners. The CFSE dilution assay revealed that dendritic cells fed with CM-EE-treated breast cancer cells successfully stimulated tumor-specific T cell proliferation without inhibiting DC function and T cell proliferation. The expression of PD-L1 mRNA and protein level was increased in dose-dependent manners. In addition, CM-EE also potentiated the cytotoxic activity of tumor-specific T cells. CM-EE can induce immunogenic and apoptotic cell death in breast cancer cells, and it is a good candidate for cancer immunotherapy and may improve the efficacy of immune checkpoint inhibitors.

scholarly journals HDAC3–ERα Selectively Regulates TNF-α-Induced Apoptotic Cell Death in MCF-7 Human Breast Cancer Cells via the p53 Signaling Pathway

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1280
Author(s):  
Seung-Ho Park ◽  
Hyunhee Kim ◽  
Sungmin Kwak ◽  
Ji-Hoon Jeong ◽  
Jangho Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Apoptotic Cell ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Tnf Α ◽  
Mcf 7

Tumor necrosis factor-α (TNF-α) plays a significant role in inflammation and cancer-related apoptosis. We identified a TNF-α-mediated epigenetic mechanism of apoptotic cell death regulation in estrogen receptor-α (ERα)-positive human breast cancer cells. To assess the apoptotic effect of TNF-α, annexin V/ propidium iodide (PI) double staining, cell viability assays, and Western blotting were performed. To elucidate this mechanism, histone deacetylase (HDAC) activity assay and immunoprecipitation (IP) were conducted; the mechanism was subsequently confirmed through chromatin IP (ChIP) assays. Finally, we assessed HDAC3–ERα-mediated apoptotic cell death after TNF-α treatment in ERα-positive human breast cancer (MCF-7) cells via the transcriptional activation of p53 target genes using luciferase assay and quantitative reverse transcription PCR. The TNF-α-induced selective apoptosis in MCF-7 cells was negatively regulated by the HDAC3–ERα complex in a caspase-7-dependent manner. HDAC3 possessed a p53-binding element, thus suppressing the transcriptional activity of its target genes. In contrast, MCF-7 cell treatment with TNF-α led to dissociation of the HDAC3–ERα complex and substitution of the occupancy on the promoter by the p53–p300 complex, thus accelerating p53 target gene expression. In this process, p53 stabilization was accompanied by its acetylation. This study showed that p53-mediated apoptosis in ERα-positive human breast cancer cells was negatively regulated by HDAC3–ERα in a caspase-7-dependent manner. Therefore, these proteins have potential application in therapeutic strategies.

scholarly journals Increased Oxidative Stress Induced by Rubus Bioactive Compounds Induce Apoptotic Cell Death in Human Breast Cancer Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-18 ◽  
Author(s):  
Blassan P. George ◽  
Heidi Abrahamse
Keyword(s):  
Breast Cancer ◽  
Oxidative Stress ◽  
Cell Death ◽  
Cytochrome C ◽  
Cancer Cells ◽  
Bioactive Compounds ◽  
Breast Cancer Cells ◽  
Apoptotic Cell ◽  
Ros Production ◽  
Caspase 9

Bioactive compounds from plants represent good candidate drugs for the prevention and treatment of various forms of cancer. Berries are rich sources of bioactive compounds, and there has been an increasing interest in the study of therapeutic action of wild berries. Oxidants are generated continuously in biological system as a result of physiological process. When there is an imbalance between oxidants and antioxidants, it leads to a condition called oxidative stress. Natural compounds as inducers of oxidative stress are able to modulate the physiological functions of cancer cells leading to cell death or survival. The aim of this study was to evaluate the induction of apoptosis by isolated bioactive compounds (1-(2-hydroxyphenyl)-4-methylpentan-1-one (C1) and 2-[(3-methylbutoxy) carbonyl] benzoic acid (C2)) from Rubus fairholmianus against MCF-7 breast cancer cells. The exposure of C1 and C2 reduced viability (IC50 of C1: 4.69; C2: 8.36 μg/mL) and proliferation. Cytochrome c release from mitochondria and changes in mitochondrial membrane potential of treated cells supported the intrinsic apoptotic cell death. Reactive oxygen species (ROS) production after treatment with C1 and C2 was found to be higher and induced nuclear damage. Expression of apoptotic proteins after the treatments was significantly upregulated as indicated using immunofluorescence (caspase 9, p53, and Bax), western blotting (p53, cleaved PARP, cytochrome c, and Bax), and ELISA (caspase 9) analysis. Overall, C1 was more cytotoxic, increased the ROS production in dichlorodihydrofluorescein diacetate assay, and induced apoptosis in breast cancer cells. These results illustrate that berry bioactive compounds have strong chemopreventive potential. In this article, we provide information on prooxidant and anticancer activities of Rubus bioactive compounds. Natural products have always demonstrated a significant contribution to the development of several cancer chemotherapeutic drugs. Most of these compounds are known to affect the redox state of the cell; and studies on these compounds have focused on their antioxidant property instead of prooxidant properties.

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