scholarly journals Salubrinal Exposes Anticancer Properties in Inflammatory Breast Cancer Cells by Manipulating the Endoplasmic Reticulum Stress Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Andrew Alsterda ◽  
Kumari Asha ◽  
Olivia Powrozek ◽  
Miroslava Repak ◽  
Sudeshna Goswami ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Tumor Microenvironment ◽  
Er Stress ◽  
Cancer Cells ◽  
Inflammatory Breast Cancer ◽  
Caspase 3 ◽  
Binding Protein

The endoplasmic reticulum (ER) regulates protein folding, post-translational modifications, lipid synthesis, and calcium signaling to attenuate the accumulation of misfolded proteins causing ER stress and maintains cellular homeostasis. The tumor microenvironment is rich in soluble cytokines, chemokines, growth, and angiogenic factors and can drive the ER’s abnormal functioning in healthy cells. Cancer cells adapt well to the tumor microenvironment induced ER stress. We identified that the inflammatory breast cancer (IBC) cells abundantly express osteoprotegerin (OPG) and their tumor microenvironment is rich in OPG protein. OPG also called osteoclast differentiation factor/osteoclastogenesis inhibitory factor (OCIF) is a soluble decoy receptor for receptor activator of nuclear factor-kappa B ligand (RANKL). Employing mass spectrometry analysis, we identified a set of ER chaperones associated with OPG in IBC cell lysates (SUM149PT, SUM1315MO2) compared to healthy human mammary epithelial cells (HMEC). Proximity ligation assay (PLA) and immunoprecipitation assay validated the interaction between OPG and ER chaperone and master regulator of unfolded protein response (UPR) GRP78/BiP (glucose-regulated protein/Binding immunoglobulin protein). We detected remarkably high gene expression of CCAAT enhancer-binding protein homologous protein (CHOP), inositol-requiring enzyme 1 (IRE1α), protein disulfide-isomerase (PDI), PKR-like ER kinase (PERK), activating transcription factor 4 (ATF4), X-box binding protein 1 (XBP-1) and growth arrest and DNA damage-inducible protein (GADD34) in SUM149PT and SUM190PT cells when compared to HMEC. Similarly, tissue sections of human IBC expressed high levels of ER stress proteins. We evaluated cell death and apoptosis upon Salubrinal and phenylbutyrate treatment in healthy and IBC cells by caspase-3 activity and cleaved poly (ADP-ribose) polymerase (PARP) protein assay. IBC (SUM149PT and SUM190PT) cells were chemosensitive to Salubrinal treatment, possibly via inhibition in OPG secretion, upregulating ATF4, and CHOP, thus ultimately driving caspase-3 mediated IBC cell death. Salubrinal treatment upregulated PDI, which connects ER stress to oxidative stress. We observed increased ROS production and reduced cell proliferation of Salubrinal treated IBC cells. Treatment with antioxidants could rescue IBC cells from ROS and aborted cell proliferation. Our findings implicate that manipulating ER stress with Salubrinal may provide a safer and tailored strategy to target the growth of inflammatory and aggressive forms of breast cancer.

scholarly journals L-Ascorbic Acid Inhibits Breast Cancer Growth by Inducing IRE/JNK/CHOP-Related Endoplasmic Reticulum Stress-Mediated p62/SQSTM1 Accumulation in the Nucleus

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1351 ◽  
Author(s):  
Youn Kyung Choi ◽  
Jung-Il Kang ◽  
Sanghoon Han ◽  
Young Ree Kim ◽  
Jaemin Jo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Ascorbic Acid ◽  
Er Stress ◽  
Cancer Cells ◽  
Cancer Growth ◽  
Autophagic Flux ◽  
Sequestosome 1 ◽  
Breast Cancer Growth

Anticancer effects of L-ascorbic acid (Vitamin C, L-AA) have been reported in various types of cancers. L-AA intake reduces breast cancer recurrence and mortality; however, the role of L-AA in the treatment of breast cancer remains poorly understood. In this study, we investigated the effect and mechanism action of L-AA on breast cancer growth. L-AA inhibited the growth of breast cancer cells by inducing apoptotic cell death at the evaluated treatment concentrations without affecting normal cells. Moreover, L-AA induces autophagosome formation via regulation of mammalian target of rapamycin (mTOR), Beclin1, and autophagy-related genes (ATGs) and increased autophagic flux. Notably, we observed that L-AA increased p62/SQSTM1 (sequestosome 1) protein levels. Accumulation of p62 protein in cancer cells in response to stress has been reported, but its role in cancer regulation remains controversial. Here, we demonstrated that L-AA-induced p62 accumulation is related to L-AA-induced breast cancer growth inhibition. Furthermore, L-AA induced endoplasmic reticulum (ER) stress via the IRE–JNK–CHOP (inositol-requiring endonuclease–c-Jun N-terminal kinase–C/EBP homologous protein) signaling pathways, which increased the nuclear levels of p62/SQSTM1. These findings provide evidence that L-AA-induced ER stress could be crucial for p62 accumulation-dependent cell death, and L-AA can be useful in breast cancer treatment.

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.

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

2017 ◽  
Vol 95 (2) ◽  
pp. 289-294 ◽  
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.

γ-Tocotrienol-induced endoplasmic reticulum stress and autophagy act concurrently to promote breast cancer cell death

2015 ◽  
Vol 93 (4) ◽  
pp. 306-320 ◽  
Author(s):  
Roshan V. Tiwari ◽  
Parash Parajuli ◽  
Paul W. Sylvester
Keyword(s):  
Breast Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cancer Cell ◽  
Human Breast Cancer ◽  
Beclin 1 ◽  
Time Dependent ◽  
Human Breast ◽  
Cancer Cell Death

The anticancer effects of γ-tocotrienol are associated with the induction of autophagy and endoplasmic reticulum (ER) stress-mediated apoptosis, but a direct relationship between these events has not been established. Treatment with 40 μmol/L of γ-tocotrienol caused a time-dependent decrease in cancer cell viability that corresponds to a concurrent increase in autophagic and endoplasmic reticulum (ER) stress markers in MCF-7 and MDA-MB-231 human breast cancer cells. γ-Tocotrienol treatment was found to cause a time-dependent increase in early phase (Beclin-1, LC3B-II) and late phase (LAMP-1 and cathepsin-D) autophagy markers, and pretreatment with autophagy inhibitors Beclin-1 siRNA, 3-MA or Baf1 blocked these effects. Furthermore, blockage of γ-tocotrienol-induced autophagy with Beclin-1 siRNA, 3-MA, or Baf1 induced a modest, but significant, reduction in γ-tocotrienol-induced cytotoxicity. γ-Tocotrienol treatment was also found to cause a decrease in mitogenic Erk1/2 signaling, an increase in stress-dependent p38 and JNK1/2 signaling, as well as an increase in ER stress apoptotic markers, including phospho-PERK, phospho-eIF2α, Bip, IRE1α, ATF-4, CHOP, and TRB3. In summary, these finding demonstrate that γ-tocotrienol-induced ER stress and autophagy occur concurrently, and together act to promote human breast cancer cell death.

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 Induction of Paraptotic Cell Death in Breast Cancer Cells by a Novel Pyrazolo[3,4-h]quinoline Derivative through ROS Production and Endoplasmic Reticulum Stress

Antioxidants ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 117
Author(s):  
Phuong Linh Nguyen ◽  
Chang Hoon Lee ◽  
Heesoon Lee ◽  
Jungsook Cho
Keyword(s):  
Breast Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Quinoline Derivative ◽  
Ros Generation ◽  
Protein Accumulation ◽  
Potential Candidate ◽  
Development Of Resistance

Chemotherapy has been a standard intervention for a variety of cancers to impede tumor growth, mainly by inducing apoptosis. However, development of resistance to this regimen has led to a growing interest and demand for drugs targeting alternative cell death modes, such as paraptosis. Here, we designed and synthesized a novel derivative of a pyrazolo[3,4-h]quinoline scaffold (YRL1091), evaluated its cytotoxic effect, and elucidated the underlying molecular mechanisms of cell death in MDA-MB-231 and MCF-7 breast cancer (BC) cells. We found that YRL1091 induced cytotoxicity in these cells with numerous cytoplasmic vacuoles, one of the distinct characteristics of paraptosis. YRL1091-treated BC cells displayed several other distinguishing features of paraptosis, excluding autophagy or apoptosis. Briefly, YRL1091-induced cell death was associated with upregulation of microtubule-associated protein 1 light chain 3B, downregulation of multifunctional adapter protein Alix, and activation of extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinase. Furthermore, the production of reactive oxygen species (ROS) and newly synthesized proteins were also observed, subsequently causing ubiquitinated protein accumulation and endoplasmic reticulum (ER) stress. Collectively, these results indicate that YRL1091 induces paraptosis in BC cells through ROS generation and ER stress. Therefore, YRL1091 can serve as a potential candidate for the development of a novel anticancer drug triggering paraptosis, which may provide benefit for the treatment of cancers resistant to conventional chemotherapy.

scholarly journals Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4173
Author(s):  
Faustino Mollinedo ◽  
Consuelo Gajate
Keyword(s):  
Pancreatic Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Apoptotic Cell ◽  
Ether Lipid ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.

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

Proceedings ◽  
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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