Tunicamycin-induced ER stress in breast cancer cells neither expresses GRP78 on the surface nor secretes it into the media

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.

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High concentration calcitriol induces endoplasmic reticulum stress related gene profile in breast cancer cells

Biochemistry and Cell Biology ◽

10.1139/bcb-2016-0037 ◽

2017 ◽

Vol 95 (2) ◽

pp. 289-294 ◽

Cited By ~ 7

Author(s):

Ali Burak Ozkaya ◽

Handan Ak ◽

Hikmet Hakan Aydin

Keyword(s):

Breast Cancer ◽

Vitamin D ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Survival Function ◽

Active Form ◽

Breast Cancer Cell Lines ◽

Transcriptomic Profile

Calcitriol, the active form of vitamin D, is known for its anticancer properties including induction of apoptosis as well as the inhibition of angiogenesis and metastasis. Understanding the mechanisms of action for calcitriol will help with the development of novel treatment strategies. Since vitamin D exerts its cellular actions via binding to its receptor and by altering expressions of a set of genes, we aimed to evaluate the effect of calcitriol on transcriptomic profile of breast cancer cells. We previously demonstrated that calcitriol alters endoplasmic reticulum (ER) stress markers, therefore in this study we have focused on ER-stress-related genes to reveal calcitriols action on these genes in particular. We have treated breast cancer cell lines MCF-7 and MDA-MB-231 with previously determined IC50 concentrations of calcitriol and evaluated the transcriptomic alterations via microarray. During analysis, only genes altered by at least 2-fold with a P value < 0.05 were taken into consideration. Our findings revealed an ER-stress-associated transcriptomic profile induced by calcitriol. Induced genes include genes with a pro-survival function (NUPR1, DNAJB9, HMOX1, LCN2, and LAMP3) and with a pro-death function (CHOP (DDIT3), DDIT4, NDGR1, NOXA, and CLGN). These results suggest that calcitriol induces an ER-stress-like response inducing both pro-survival and pro-death transcripts in the process.

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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

10.21203/rs.3.rs-273844/v1 ◽

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.

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Knockdown of TM9SF4 triggering ER stress exerts anti‐growth effect on drug‐resistant breast cancer cells

The FASEB Journal ◽

10.1096/fasebj.2018.32.1_supplement.804.6 ◽

2018 ◽

Vol 32 (S1) ◽

Author(s):

Yifei Zhu ◽

Xiaoqiang Yao

Keyword(s):

Breast Cancer ◽

Er Stress ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Growth Effect ◽

Drug Resistant

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Bafilomycin Prevented Curcumin-Induced Endoplasmic Reticulum (ER) Stress and Autophagy in MCF-7 Growth Hormone Positive (GH+) Breast Cancer Cells

Proceedings ◽

10.3390/proceedings2251568 ◽

2018 ◽

Vol 2 (25) ◽

pp. 1568

Author(s):

Merve Karataş ◽

Ajda Coker-Gurkan ◽

Elif Damla Arisan ◽

Pınar Obakan-Yerlikaya ◽

Narcin Palavan-Unsal

Keyword(s):

Breast Cancer ◽

Growth Hormone ◽

Endoplasmic Reticulum ◽

Cell Viability ◽

Er Stress ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Time Dependent ◽

Dependent Manner ◽

Mcf 7

Autocrine growth hormone (GH) induced cell proliferation, invasion-metastasis and drug resistance in breast cancer cells. Curcumin has an apoptotic effect on colon, melanoma, cervix, and breast cancer cells. Autophagy and endoplasmic reticulum (ER) stress are essential cellular processes activated under nutrient deprivation, pathogen infection and drug exposure. Our aim in this study is to investigate the time-dependent effect of curcumin on ER stress and autophagy and potential increase of curcumin efficiency by bafilomycin treatment. Autocrine GH expression triggered resistant profile against curcumin-induced cell viability loss in MCF-7 cells. However, this effect was prevented by the time-dependent manner in MCF-7 cells. In GH+ breast cancer cells bafilomycin increase curcumin-induced cell viability loss by MTT cell viability assay. In conclusion, autocrine GH-triggered curcumin resistance was overcome by autophagy inhibition condition by bafilomycin treatment in a dose-dependent manner in MCF-7 GH+ breast cancer cells.

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Crosstalk of ER Stress, Mitochondrial Membrane Potential and ROS Determines Cell Death Mechanisms Induced by Etoposide Loaded GelatinNanoparticles in MCF-7 Breast Cancer Cells

Journal of Nanomedicine & Nanotechnology ◽

10.4172/2157-7439.1000513 ◽

2018 ◽

Vol 09 (04) ◽

Author(s):

Anita K. Verma ◽

Imran Moin ◽

Largee Biswas ◽

Disha Mittal ◽

Ankita Leekha ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Membrane Potential ◽

Er Stress ◽

Cancer Cells ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Membrane ◽

Breast Cancer Cells ◽

Cell Death Mechanisms ◽

Mcf 7

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Pygenic Acid A (PA) Sensitizes Metastatic Breast Cancer Cells to Anoikis and Inhibits Metastasis In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms21228444 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8444

Author(s):

Ga-Eun Lim ◽

Jee Young Sung ◽

Suyeun Yu ◽

Younmi Kim ◽

Jaegal Shim ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Er Stress ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Metastatic Breast ◽

Breast Cancer Cell Lines ◽

Syngeneic Mouse Model ◽

Apoptosis Protein ◽

4T1 Cells

Metastasis is the main cause of cancer-related deaths. Anoikis is a type of apoptosis caused by cell detachment, and cancer cells become anoikis resistant such that they survive during circulation and can successfully metastasize. Therefore, sensitization of cancer cells to anoikis could prevent metastasis. Here, by screening for anoikis sensitizer using natural compounds, we found that pygenic acid A (PA), a natural compound from Prunella vulgaris, not only induced apoptosis but also sensitized the metastatic triple-negative breast cancer cell lines, MDA-MB-231 cells (human) and 4T1 cells (mouse), to anoikis. Apoptosis protein array and immunoblotting analysis revealed that PA downregulated the pro-survival proteins, including cIAP1, cIAP2, and survivin, leading to cell death of both attached and suspended cells. Interestingly, PA decreased the levels of proteins associated with anoikis resistance, including p21, cyclin D1, p-STAT3, and HO-1. Ectopic expression of active STAT3 attenuated PA-induced anoikis sensitivity. Although PA activated ER stress and autophagy, as determined by increases in the levels of characteristic markers, such as IRE1α, p-elF2α, LC3B I, and LC3B II, PA treatment resulted in p62 accumulation, which could be due to PA-induced defects in autophagy flux. PA also decreased metastatic characteristics, such as cell invasion, migration, wound closure, and 3D growth. Finally, lung metastasis of luciferase-labeled 4T1 cells decreased following PA treatment in a syngeneic mouse model when compared with the control. These data suggest that PA sensitizes metastatic breast cancer cells to anoikis via multiple pathways, such as inhibition of pro-survival pathways and activation of ER stress and autophagy, leading to the inhibition of metastasis. These findings suggest that sensitization to anoikis by PA could be used as a new therapeutic strategy to control the metastasis of breast cancer.

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