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.

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.

Pyridoxine Preferentially Induces Auditory Neuropathy Through Mitochondrial Dysfunction and Endoplasmic Reticulum Stress-Mediated Apoptosis

2019 ◽  
Vol 128 (6_suppl) ◽  
pp. 117S-124S ◽  
Author(s):  
Channy Park ◽  
Hyewon Lim ◽  
Sung K. Moon ◽  
Raekil Park
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Protein Expression ◽  
Er Stress ◽  
Nerve Fiber ◽  
Apoptotic Cell ◽  
Auditory Neuropathy ◽  
Parp Cleavage ◽  
Ros Generation ◽  
Ganglion Neurons

Objectives: Auditory neuropathy due to toxicity mechanism of pyridoxine has not yet been fully documented. Therefore, the present study explored a direct mechanism underlying the effects of pyridoxine on auditory neuropathy in organ of Corti (OC) explants ex vivo and cochlear neuroblast cell line, VOT-33 in vitro. Methods: Primary OC explants containing spiral ganglion neurons and cultured VOT-33 cells were treated with pyridoxine. Results: In nerve fiber of primary OC explants, pyridoxine decreased staining for NF200, a neuro-cytoskeletal protein. We also found that pyridoxine-induced VOT-33 apoptosis, as indicated by accumulation of the sub-G0/G1 fraction, caspase-3 activation, and PARP cleavage. In addition, pyridoxine induced reactive oxygen species (ROS) generation and alteration of mitochondrial membrane potential transition (MPT), including Bcl-2 family protein expression and consequently Ca2+ accumulation and changes of endoplasmic reticulum (ER) stress-related protein expression such as phospho-PERK, caspase-12, Grp78, and CHOP. Conclusion: Pyridoxine preferentially induced severe cell death on nerve fiber in primary OC explants and markedly increased apoptotic cell death via mitochondria-mediated ER stress in VOT-33 cells.

New Insight into Triple-Negative Breast Cancer Therapy: The Potential Roles of Endoplasmic Reticulum Stress and Autophagy Mechanisms

2020 ◽  
Vol 20 ◽  
Author(s):  
Milad Ashrafizadeh ◽  
Reza Mohammadinejad ◽  
Shima Tavakol ◽  
Zahra Ahmadi ◽  
Amihossein Sahebkar
Keyword(s):  
Breast Cancer ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Tumor Cells ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Cancer Mortality ◽  
Autophagic Cell Death ◽  
Cancer Pathology

Background: Breast cancer is accounted as the fifth leading cause of mortality among the other cancers. Notwithstanding, Triple Negative Breast Cancer (TNBC) is responsible for the 15-20% of breast cancer mortality. Despite the many investigations, it remains incurable in part due to insufficient understanding of its exact mechanisms. Methods: A literature search was performed in PubMed, SCOPUS and Web of Science databases using the keywords autophagy, Endoplasmic Reticulum (ER) stress, apoptosis, TNBC and the combinations of these keywords. Results: It was found that autophagy plays a dual role in cancer, so that it may decrease the viability of tumor cells or act as a cytoprotective mechanism. It then appears that using compounds having modulatory effects on autophagy is of importance in terms of induction of autophagic cell death and diminishing the proliferation and metastasis of tumor cells. Also, ER stress can be modulated in order to stimulate apoptotic and autophagic cell death in tumor cells. Conclusion: Perturbation in the signaling pathways related to cell survival leads to the initiation and progression of cancer. Regarding the advancement in the cancer pathology, it seems that modulation of autophagy and ER stress are promising.

Capsaicin mediates apoptosis in human nasopharyngeal carcinoma NPC-TW 039 cells through mitochondrial depolarization and endoplasmic reticulum stress

2011 ◽  
Vol 31 (6) ◽  
pp. 539-549 ◽  
Author(s):  
S-W Ip ◽  
S-H Lan ◽  
H-F Lu ◽  
A-C Huang ◽  
J-S Yang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Nasopharyngeal Carcinoma ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Dependent Manner ◽  
Mitochondrial Depolarization ◽  
Human Nasopharyngeal Carcinoma ◽  
Induced Apoptosis

Capsaicin, a pungent compound found in hot chili peppers, has been reported to have antitumor activities in many human cancer cell lines, but the induction of precise apoptosis signaling pathway in human nasopharyngeal carcinoma (NPC) cells is unclear. Here, we investigated the molecular mechanisms of capsaicin-induced apoptosis in human NPC, NPC-TW 039, cells. Effects of capsaicin involved endoplasmic reticulum (ER) stress, caspase-3 activation and mitochondrial depolarization. Capsaicin-induced cytotoxic effects (cell death) through G0/G1 phase arrest and induction of apoptosis of NPC-TW 039 cells in a dose-dependent manner. Capsaicin treatment triggered ER stress by promoting the production of reactive oxygen species (ROS), increasing levels of inositol-requiring 1 enzyme (IRE1), growth arrest and DNA-damage-inducible 153 (GADD153) and glucose-regulated protein 78 (GRP78). Other effects included an increase in cytosolic Ca2+, loss of the mitochondrial transmembrane potential (ΔΨ m), releases of cytochrome c and apoptosis-inducing factor (AIF), and activation of caspase-9 and -3. Furthermore, capsaicin induced increases in the ratio of Bax/Bcl-2 and abundance of apoptosis-related protein levels. These results suggest that ER stress- and mitochondria-mediated cell death is involved in capsaicin-induced apoptosis in NPC-TW 039 cells.

scholarly journals Protective Mechanisms of the Mitochondrial-Derived Peptide Humanin in Oxidative and Endoplasmic Reticulum Stress in RPE Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Leonid Minasyan ◽  
Parameswaran G. Sreekumar ◽  
David R. Hinton ◽  
Ram Kannan
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Apoptotic Cell ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Ros Generation ◽  
Rpe Cells ◽  
Age Related

Age-related macular degeneration (AMD) is the leading cause of severe and irreversible vision loss and is characterized by progressive degeneration of the retina resulting in loss of central vision. The retinal pigment epithelium (RPE) is a critical site of pathology of AMD. Mitochondria and the endoplasmic reticulum which lie in close anatomic proximity to each other are targets of oxidative stress and endoplasmic reticulum (ER) stress, respectively, and contribute to the progression of AMD. The two organelles exhibit close interactive function via various signaling mechanisms. Evidence for ER-mitochondrial crosstalk in RPE under ER stress and signaling pathways of apoptotic cell death is presented. The role of humanin (HN), a prominent member of a newly discovered family of mitochondrial-derived peptides (MDPs) expressed from an open reading frame of mitochondrial 16S rRNA, in modulation of ER and oxidative stress in RPE is discussed. HN protected RPE cells from oxidative and ER stress-induced cell death by upregulation of mitochondrial GSH, inhibition of ROS generation, and caspase 3 and 4 activation. The underlying mechanisms of ER-mitochondrial crosstalk and modulation by exogenous HN are discussed. The therapeutic use of HN and related MDPs could potentially prove to be a valuable approach for treatment of AMD.

scholarly journals Sophorolipid exhibits antifungal activity by ROS mediated endoplasmic reticulum stress and mitochondrial dysfunction pathways in Candida albicans

RSC Advances ◽  
2019 ◽  
Vol 9 (71) ◽  
pp. 41639-41648 ◽  
Author(s):  
Farazul Haque ◽  
Nitish Kumar Verma ◽  
Mohammad Alfatah ◽  
Swati Bijlani ◽  
Mani Shankar Bhattacharyya
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Ros Generation

Sophorolipid induces ROS generation in C. albicans leading to mitochondrial dysfunction and ER stress followed by the release of Ca2+ ions (from the ER lumen) that enter mitochondria and further magnify ROS generation leading to cell death.

Abstract P085: Microrna Profiling Of Vascular Smooth Muscle Cells In Human Hypertension Potential Regulators Of Endoplasmic Reticulum And Oxidative Stress

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
YU WANG ◽  
Livia Camargo ◽  
Wendy Beatie ◽  
Martin McBride ◽  
Augusto C Montezano ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Stress Proteins ◽  
Target Prediction ◽  
Fold Change ◽  
Ros Generation ◽  
Human Hypertension ◽  
Mirna Array

Numerous molecular mechanisms have been implicated in processes underlying vascular phenotypic changes and alterations in hypertension, including microRNAs (miRNAs), oxidative stress and perturbed endoplasmic reticulum (ER) function. The interplay between these elements is unclear. We assessed the VSMC miRNAs profile in hypertension focusing on oxidative and ER stress pathways. VSMCs from small arteries from normotensive (NT) and hypertensive (HT) subjects were used. miRNA profiling of 758 miRNAs was performed using TaqMan advanced miRNA assay (TaqMan Low Density Array Human microRNA). Ingenuity Pathway Analysis (IPA) was used for miRNA target prediction. Expression of vascular genes and proteins was detected by RT-PCR and immunoblotting. ROS generation (chemiluminescence) was assessed in the absence and presence of ER stress inducer tunicamycin (5μg/ml, 24h). miRNA array identified 25 miRNAs uniquely expressed in HT and 21 miRNAs uniquely expressed in NT (CT<30). Of the 332 miRNAs present in both groups, 60 miRNAs were significantly upregulated in HT (fold change >1.5), while 136 miRNAs were significantly downregulated in HT (fold change >1.5). miRNAs that were altered in hypertension, targeted genes involved in oxidative and ER stress. Pro-oxidant [Nox1 mRNA (1.71 fold), Nox4 (1.59 fold), Nox5 (2.04 fold)] and antioxidant [SOD2 mRNA (4.43 fold), GPx1 (1.97 fold)] enzymes protein levels upregulated in HT (p<0.05 vs NT). ER stress proteins, such as PERK (1.57 fold) and elF2α (2.31 fold) were also upregulated in HT (p<0.05 vs NT). IPA analysis of our miRNA library, revealed that miR-505-5p (-2.13 fold), miR-324-5p (-1.51 fold), miR-185-5p (-1.742 fold) and miR-491-5p (-1.667 fold) may regulate Nox5 levels. Moreover, miR-200b-3p (-28.57 fold) targets multiple ER stress pathways including elF2α. Treatment with tunicamycin increased ROS generation (2.29 fold) and Nox5 protein expression (1.69 fold) while downregulating SOD2 mRNA (-8.02 fold) in HT (p<0.05 vs NT). Our findings unveil the differentially expressed miRNAs and their predicted redox targets, highlighting potential interplay between VSMC ER stress, oxidative stress and miRNAs in human hypertension.

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 Endoplasmic Reticulum Stress and Diabetic Cardiomyopathy

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Jiancheng Xu ◽  
Qi Zhou ◽  
Wei Xu ◽  
Lu Cai
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Diabetic Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Lipid Synthesis ◽  
The Unfolded Protein Response ◽  
Cell Stress Response

The endoplasmic reticulum (ER) is an organelle entrusted with lipid synthesis, calcium homeostasis, protein folding, and maturation. Perturbation of ER-associated functions results in an evolutionarily conserved cell stress response, the unfolded protein response (UPR) that is also called ER stress. ER stress is aimed initially at compensating for damage but can eventually trigger cell death if ER stress is excessive or prolonged. Now the ER stress has been associated with numerous diseases. For instance, our recent studies have demonstrated the important role of ER stress in diabetes-induced cardiac cell death. It is known that apoptosis has been considered to play a critical role in diabetic cardiomyopathy. Therefore, this paper will summarize the information from the literature and our own studies to focus on the pathological role of ER stress in the development of diabetic cardiomyopathy. Improved understanding of the molecular mechanisms underlying UPR activation and ER-initiated apoptosis in diabetic cardiomyopathy will provide us with new targets for drug discovery and therapeutic intervention.

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.

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