scholarly journals Recovering Drug-Induced Apoptosis Subnetwork from Connectivity Map Data

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Jiyang Yu ◽  
Preeti Putcha ◽  
Jose M. Silva
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Specific Cell ◽  
Connectivity Map ◽  
Drug Induced ◽  
Significant Differential Expression ◽  
Apoptosis Pathway ◽  
Cell Death Pathways ◽  
Intrinsic Apoptosis Pathway ◽  
Extrinsic Apoptosis

The Connectivity Map (CMAP) project profiled human cancer cell lines exposed to a library of anticancer compounds with the goal of connecting cancer with underlying genes and potential treatments. Since the therapeutic goal of most anticancer drugs is to induce tumor-selective apoptosis, it is critical to understand the specific cell death pathways triggered by drugs. This can help to better understand the mechanism of how cancer cells respond to chemical stimulations and improve the treatment of human tumors. In this study, using CMAP microarray data from breast cancer cell line MCF7, we applied a Gaussian Bayesian network modeling approach and identified apoptosis as a major drug-induced cellular-pathway. We then focused on 13 apoptotic genes that showed significant differential expression across all drug-perturbed samples to reconstruct the apoptosis network. In our predicted subnetwork, 9 out of 15 high-confidence interactions were validated in the literature, and our inferred network captured two major cell death pathways by identifying BCL2L11 and PMAIP1 as key interacting players for the intrinsic apoptosis pathway and TAXBP1 and TNFAIP3 for the extrinsic apoptosis pathway. Our inferred apoptosis network also suggested the role of BCL2L11 and TNFAIP3 as “gateway” genes in the drug-induced intrinsic and extrinsic apoptosis pathways.

scholarly journals Positive allosteric modulation of P2X7 promotes apoptotic cell death over lytic cell death responses in macrophages

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Stefan Bidula ◽  
Kshitija Dhuna ◽  
Ray Helliwell ◽  
Leanne Stokes
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Caspase 3 ◽  
Allosteric Modulation ◽  
Cell Swelling ◽  
Dependent Manner ◽  
Apoptosis Pathway ◽  
Membrane Rupture ◽  
Cell Death Pathways ◽  
Intrinsic Apoptosis Pathway

AbstractP2X7 is an ATP-gated ion channel that is highly expressed by leukocytes, such as macrophages. Here, P2X7 has been demonstrated to be involved in the regulation of various cell death pathways; including apoptosis, pyroptosis, necrosis, and autophagy. However, cell death induction via P2X7 is complex and is reliant upon the nature of the stimulus, the duration of the stimulus, and the cell type investigated. Previous reports state that high extracellular ATP concentrations promote osmotic lysis, but whether positive allosteric modulation of P2X7 in the presence of lower concentrations of ATP condemns cells to the same fate is unknown. In this study, we compared cell death induced by high ATP concentrations, to cell death induced by compound K, a recently identified and potent positive allosteric modulator of P2X7. Based on our observations, we propose that high ATP concentrations induce early cell swelling, loss of mitochondrial membrane potential, plasma membrane rupture, and LDH release. Conversely, positive allosteric modulation of P2X7 primarily promotes an intrinsic apoptosis pathway. This was characterised by an increase in mitochondrial Ca2+, accelerated production of mitochondrial ROS, loss of mitochondrial membrane permeability in a Bax-dependent manner, the potential involvement of caspase-1, and caspase-3, and significantly accelerated kinetics of caspase-3 activation. This study highlights the ability of positive allosteric modulators to calibrate P2X7-dependent cell death pathways and may have important implications in modulating the antimicrobial immune response and in the resolution of inflammation.

scholarly journals Analysis of BNIP3 and BNIP3L/Nix expression in cybrid cell lines harboring two LHON-associated mutations.

2019 ◽  
Author(s):  
Agata Kodroń ◽  
Parvana Hajieva ◽  
Agata Kulicka ◽  
Bohdan Paterczyk ◽  
Elona Jankauskaite ◽  
...  
Keyword(s):  
Cell Death ◽  
Optic Nerve ◽  
Cellular Response ◽  
Nerve Degeneration ◽  
Apoptosis Pathway ◽  
Mtdna Mutations ◽  
Cell Death Pathways ◽  
Intrinsic Apoptosis Pathway ◽  
Response To Stress ◽  
In Cells

Mitochondria are key players in cell death through the activation of the intrinsic apoptosis pathway. BNIP3 and BNIP3L/Nix are outer mitochondrial membrane bifunctional proteins which because of containing both BH3 and LIR domains play a role in cellular response to stress by regulation of apoptosis and selective autophagy. Leber’s Hereditary Optic Neuropathy (LHON) is the most common mitochondrial disease in adults, characterized by painless loss of vision caused by atrophy of the optic nerve. The disease in over 90% of cases is caused by one of three mutations in the mitochondrial genome: 11778G>A, 3460G>A or 14484T>C. The pathogenic processes leading to optic nerve degeneration are largely unknown, however, the most common explanation is that mtDNA mutations increase the apoptosis level in this tissue. Here we present the results of analysis of BNIP3 and BNIP3L/Nix proteins in cells harboring a combination of the 11778G>A and the 3460G>A LHON mutations. Experiments performed on cybrids revealed that BNIP3 protein level is decreased in LHON cells compared to controls. CCCP treatment resulted in apoptosis induction only in control cells. Moreover, we also noticed reduced level of autophagy in LHON cybrids. The presented results suggest that in cells carrying LHON mutations expression of proteins involved in regulation of apoptosis and autophagy is decreased what in turn may disturb cell death pathways in those cells and affect cellular response to stress.  

scholarly journals Progress in understanding the role of lncRNA in programmed cell death

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Na Jiang ◽  
Xiaoyu Zhang ◽  
Xuejun Gu ◽  
Xiaozhuang Li ◽  
Lei Shang
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Molecular Mechanisms ◽  
Membrane Receptors ◽  
Gene Expressions ◽  
Apoptosis Pathway ◽  
Stem Cell Pluripotency ◽  
Extrinsic Apoptosis ◽  
Related Proteins ◽  
Cycle Regulation

AbstractLong non-coding RNAs (lncRNAs) are transcripts longer than 200 nucleotides but not translated into proteins. LncRNAs regulate gene expressions at multiple levels, such as chromatin, transcription, and post-transcription. Further, lncRNAs participate in various biological processes such as cell differentiation, cell cycle regulation, and maintenance of stem cell pluripotency. We have previously reported that lncRNAs are closely related to programmed cell death (PCD), which includes apoptosis, autophagy, necroptosis, and ferroptosis. Overexpression of lncRNA can suppress the extrinsic apoptosis pathway by downregulating of membrane receptors and protect tumor cells by inhibiting the expression of necroptosis-related proteins. Some lncRNAs can also act as competitive endogenous RNA to prevent oxidation, thereby inhibiting ferroptosis, while some are known to activate autophagy. The relationship between lncRNA and PCD has promising implications in clinical research, and reports have highlighted this relationship in various cancers such as non-small cell lung cancer and gastric cancer. This review systematically summarizes the advances in the understanding of the molecular mechanisms through which lncRNAs impact PCD.

scholarly journals Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and the Bcl-2 Protein Family

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Christopher Platen ◽  
Stephan Dreschers ◽  
Jessica Wappler ◽  
Andreas Ludwig ◽  
Stefan Düsterhöft ◽  
...  
Keyword(s):  
Cell Death ◽  
Bacterial Infections ◽  
Caspase 3 ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Dependent Manner ◽  
Intrinsic Apoptosis ◽  
Caspase 9 ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

Neonates are extremely susceptible to bacterial infections, and evidences suggest that phagocytosis-induced cell death (PICD) is less frequently triggered in neonatal monocytes than in monocytes from adult donors. An insufficient termination of the inflammatory response, leading to a prolonged survival of neonatal monocytes with ongoing proinflammatory cytokine release, could be associated with the progression of various inflammatory diseases in neonates. Our previous data indicate that amphiregulin (AREG) is increasingly expressed on the cell surface of neonatal monocytes, resulting in remarkably higher soluble AREG levels after proteolytic shedding. In this study, we found that E. coli-infected neonatal monocytes show an increased phosphorylation of ERK, increased expression of Bcl-2 and Bcl-XL, and reduced levels of cleaved caspase-3 and caspase-9 compared to adult monocytes. In both cell types, additional stimulation with soluble AREG further increased ERK activation and expression of Bcl-2 and Bcl-XL and reduced levels of cleaved caspase-3 and caspase-9 in an EGFR-dependent manner. These data suggest that reduced PICD of neonatal monocytes could be due to reduced intrinsic apoptosis and that AREG can promote protection against PICD. This reduction of the intrinsic apoptosis pathway in neonatal monocytes could be relevant for severely prolonged inflammatory responses of neonates.

scholarly journals Novel camphor-based pyrimidine derivatives induced cancer cell death through a ROS-mediated mitochondrial apoptosis pathway

RSC Advances ◽  
2019 ◽  
Vol 9 (51) ◽  
pp. 29711-29720
Author(s):  
Yan Zhang ◽  
Yunyun Wang ◽  
Yuxun Zhao ◽  
Wen Gu ◽  
Yongqiang Zhu ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Mitochondrial Apoptosis ◽  
Pyrimidine Derivatives ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
Cancer Cell Death ◽  
Anti Tumor Activity

A series of novel camphor-based pyrimidine derivatives were synthesized and characterized. We found the compound 3f exhibited strongest anti-tumor activity via ROS-mediated mitochondrial apoptosis pathway.

scholarly journals Cell death following the loss of ADAR1 mediated A-to-I RNA editing is not effected by the intrinsic apoptosis pathway

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Carl R. Walkley ◽  
Benjamin T. Kile
Keyword(s):  
Cell Death ◽  
Rna Editing ◽  
Rna Structure ◽  
Fetal Liver ◽  
Loss Of Function ◽  
Intrinsic Apoptosis ◽  
Triple Mutant ◽  
Apoptosis Pathway ◽  
Mitochondrial Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

AbstractModifications of RNA, collectively termed as the epitranscriptome, are widespread, evolutionarily conserved and contribute to gene regulation and protein diversity in healthy and disease states. There are >160 RNA modifications described, greatly exceeding the number of modifications to DNA. Of these, adenosine-to-inosine (A-to-I) RNA editing is one of the most common. There are tens of thousands of A-to-I editing sites in mouse, and millions in humans. Upon translation or sequencing an inosine base is decoded as guanosine, leading to A-to-G mismatches between the RNA and DNA. Inosine has different base pairing properties to adenosine and as a result editing not only alters the RNA code but can also change the RNA structure. In mammals A-to-I editing is performed by ADAR1 and ADAR2. A feature of murine loss of function ADAR1 alleles is cell death and a failure to survive embryogenesis. Adar1−/− and editing deficient (Adar1E861A/E861A) mice die between E11.75–13.5 of failed hematopoiesis. Strikingly this phenotype is rescued by the deletion of the cytosolic dsRNA sensor MDA5 or its downstream adaptor MAVS, a mechanism conserved in human and mouse. Current literature indicates that the loss of ADAR1 leads to cell death via apoptosis, yet this has not been genetically established. We report that blockade of the intrinsic (mitochondrial) apoptosis pathway, through the loss of both BAK and BAX, does not rescue or modify the cellular phenotype of the fetal liver or extend the lifespan of ADAR1 editing deficient embryos. We had anticipated that the loss of BAK and BAX would rescue, or at least significantly extend, the gestational viability of Adar1E861A/E861A embryos. However, the triple mutant Adar1E861A/E861ABak−/−Bax−/− embryos that were recovered at E13.5 were indistinguishable from the Adar1E861A/E861A embryos with BAK and BAX. The results indicate that cell death processes not requiring the intrinsic apoptosis pathway are triggered by MDA5 following the loss of ADAR1.

Preclinical Evaluation of the Proteasome Inhibitor MLN9708 (MLN2238) In Chronic Lymphocytic Leukemia Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4634-4634
Author(s):  
Aisha Masood ◽  
Kiersten M Miles ◽  
Nazmul H Khan ◽  
Drusilla Akhtar ◽  
Remi Adelaiye ◽  
...  
Keyword(s):  
Cell Death ◽  
Chronic Lymphocytic Leukemia ◽  
Proteasome Inhibitor ◽  
Active Form ◽  
Lymphocytic Leukemia ◽  
Biologically Active ◽  
Autologous Serum ◽  
Mitochondrial Outer Membrane ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway

Abstract Abstract 4634 The proteasome is an important therapeutic target in multiple hematological malignancies. The proteasome inhibitor bortezomib has demonstrated significant clinical activity in multiple myeloma and mantle cell lymphoma. However, clinically bortezomib has failed to demonstrate efficacy in chronic lymphocytic leukemia (CLL); the exact reason for this remains unknown. MLN9708 (Millennium Pharmaceuticals, Inc., Cambridge, MA) is a proteasome inhibitor which has a shorter proteasome dissociation half life than bortezomib and is currently in Phase I clinical development. Upon exposure to aqueous solutions or plasma, MLN9708 rapidly hydrolyzes to MLN2238, the biologically active form. MLN2238 was used for all of the studies reported here, in which we evaluated the antileukemic effects of MLN2238 in primary CLL cells from 16 patients. MLN 2238 induced a time and dose dependent decrease in CLL cell viability in 12 (75%) patient cells in vitro. Cell death was shown to be due to the induction of apoptosis confirmed by Annexin V staining of CLL cells and cleavage of PARP-1, an indicator of apoptosis. Biochemical analysis showed that caspase 3 and 9 were activated in these cells, indicating that MLN2238 induces cell death through the intrinsic apoptosis pathway. We noted increased mitochondrial outer membrane permeability (MOMP) in the presence of MLN2238, which suggests the engagement of the mitochondria in MLN2238 induced apoptosis in CLL cells. Evaluation of non-responding CLL patient samples demonstrated that increased expression of PSMB5 is associated with lack of sensitivity to MLN2238. Furthermore, incremental addition of autologous serum in responding CLL samples resulted in upregulation of PSMB5 levels, resulting in protection against MLN2238 induced cell death. Our preclinical observations demonstrate for the first time that MLN2238 can induce death in primary CLL cells, and support further investigation in CLL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Intracellular expression of arginine deiminase activates the mitochondrial apoptosis pathway through inhibiting cytosolic ferritin and inducing chromotin autophagy

2020 ◽  
Author(s):  
Qingyuan Feng ◽  
Xuzhao Bian ◽  
Xuan Liu ◽  
Ying Wang ◽  
Huiting Zhou ◽  
...  
Keyword(s):  
Cell Death ◽  
Western Blot ◽  
Cancer Cell ◽  
Malignant Tumors ◽  
Mitochondrial Damage ◽  
Arginine Deiminase ◽  
Immunofluorescent Staining ◽  
Apoptosis Pathway ◽  
P53 Expression ◽  
Cancer Cell Death

Abstract Background：Based on its low toxicity, arginine starvation therapy has the potential to treat those malignant tumors that can’t be treated by surgery. Arginine deiminase (ADI) gene is indicated to be an ideal cancer-suppressor gene. ADI expressed in cytosol displays higher oncolytic efficiency than ADI-PEG20 (Pegylated Arginine Deiminase by PEG 20,000). However, it is still unknown whether cytosolic ADI has the same function mechanism as ADI-PEG20 or other underlying mechanisms in cells.Methods: The interaction of ADI and other protein factors was screened by yeast hybrid, and verified by co-immunoprecipitation and immunofluorescent staining. The effect of ADI inhibiting ferritin light-chain domain (FTL) on mitochondrial damage was evaluated by site-directed mutation and flow cytometry. The apoptosis pathway of mitochondria control was analyzed by Western Blot and real-time PCR experiments. The effect of p53 expression on cancer cell death was assessed by siTP53 transfection. The chromatin autophagy was explored by immunofluorescent staining and Western Blot.Results: ADI expressed in cytosol inhibited the activity of cytosolic ferritin through interacting with FTL. The inactive mutant of ADI still induced the apoptosis in certain cell lines of ASS- through mitochondrial damage. Arginine starvation also induced the increased expression of p53 and p53AIP1, which aggravate cellular mitochondrial damage. Chromatin autophagy appeared at the later stage of arginine starvation. DNA damage came along with the whole process of arginine starvation. Histone 3 (H3) was found in autophagosomes, which implied that cancer cells try to utilize the arginine in histones to survive during arginine starvation. Conclusions: Mitochondrial damage is the major mechanism of cell death induced by cytosolic ADI. Chromatophagy accumulations not only drive cancer cell to utilize histone arginine but also speed up cancer cell death at the later time point of arginine starvation.

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