scholarly journals Eltrombopag directly inhibits BAX and prevents cell death

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Adam Z. Spitz ◽  
Emmanouil Zacharioudakis ◽  
Denis E. Reyna ◽  
Thomas P. Garner ◽  
Evripidis Gavathiotis
Keyword(s):  
Cell Death ◽  
Structure Function ◽  
Cellular Stress ◽  
Transformation Process ◽  
Tissue Homeostasis ◽  
Conformational Transformation ◽  
Aberrant Cell ◽  
Mitochondrial Regulation ◽  
Family Protein ◽  
Potential Therapeutics

AbstractThe BCL-2 family protein BAX has essential activity in mitochondrial regulation of cell death. While BAX activity ensures tissue homeostasis, when dysregulated it contributes to aberrant cell death in several diseases. During cellular stress BAX is transformed from an inactive cytosolic conformation to a toxic mitochondrial oligomer. Although the BAX transformation process is not well understood, drugs that interfere with this process are useful research tools and potential therapeutics. Here, we show that Eltrombopag,  an FDA-approved drug,  is a direct inhibitor of BAX. Eltrombopag binds the BAX trigger site distinctly from BAX activators, preventing them from triggering BAX conformational transformation and simultaneously promoting stabilization of the inactive BAX structure. Accordingly, Eltrombopag is capable of inhibiting BAX-mediated apoptosis induced by cytotoxic stimuli. Our data demonstrate structure-function insights into a mechanism of BAX inhibition and reveal a mechanism for Eltrombopag that may expand its use in diseases of uncontrolled cell death.

scholarly journals Autophagy Provides Nutrients but Can Lead to Chop-dependent Induction of Bim to Sensitize Growth Factor–deprived Cells to Apoptosis

2009 ◽  
Vol 20 (4) ◽  
pp. 1180-1191 ◽  
Author(s):  
Brian J. Altman ◽  
Jessica A. Wofford ◽  
Yuxing Zhao ◽  
Jonathan L. Coloff ◽  
Emily C. Ferguson ◽  
...  
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Essential Gene ◽  
Time Frame ◽  
Tissue Homeostasis ◽  
Nutrient Source ◽  
Family Protein ◽  
Mitochondrial Lipid

Tissue homeostasis is controlled by the availability of growth factors, which sustain exogenous nutrient uptake and prevent apoptosis. Although autophagy can provide an alternate intracellular nutrient source to support essential basal metabolism of apoptosis-resistant growth factor–withdrawn cells, antiapoptotic Bcl-2 family proteins can suppress autophagy in some settings. Thus, the role of autophagy and interactions between autophagy and apoptosis in growth factor–withdrawn cells expressing Bcl-2 or Bcl-xL were unclear. Here we show autophagy was rapidly induced in hematopoietic cells upon growth factor withdrawal regardless of Bcl-2 or Bcl-xL expression and led to increased mitochondrial lipid oxidation. Deficiency in autophagy-essential gene expression, however, did not lead to metabolic catastrophe and rapid death of growth factor–deprived cells. Rather, inhibition of autophagy enhanced survival of cells with moderate Bcl-2 expression for greater than 1 wk, indicating that autophagy promoted cell death in this time frame. Cell death was not autophagic, but apoptotic, and relied on Chop-dependent induction of the proapoptotic Bcl-2 family protein Bim. Therefore, although ultimately important, autophagy-derived nutrients appear initially nonessential after growth factor withdrawal. Instead, autophagy promotes tissue homeostasis by sensitizing cells to apoptosis to ensure only the most apoptosis-resistant cells survive long-term using autophagy-derived nutrients when growth factor deprived.

scholarly journals Cell Death and Metabolic Stress in Gymnodinium catenatum Induced by Allelopathy

Toxins ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 506
Author(s):  
Leyberth José Fernández-Herrera ◽  
Christine Johanna Band-Schmidt ◽  
Tania Zenteno-Savín ◽  
Ignacio Leyva-Valencia ◽  
Claudia Judith Hernández-Guerrero ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Protein Content ◽  
Caspase 3 ◽  
Cellular Stress ◽  
Allelopathic Effect ◽  
Sod Activity ◽  
Free Media ◽  
O2 Production ◽  
Gymnodinium Catenatum

Allelopathy between phytoplankton species can promote cellular stress and programmed cell death (PCD). The raphidophyte Chattonella marina var. marina, and the dinoflagellates Margalefidinium polykrikoides and Gymnodinium impudicum have allelopathic effects on Gymnodinium catenatum; however, the physiological mechanisms are unknown. We evaluated whether the allelopathic effect promotes cellular stress and activates PCD in G. catenatum. Cultures of G. catenatum were exposed to cell-free media of C. marina var. marina, M. polykrikoides and G. impudicum. The mortality, superoxide radical (O2●−) production, thiobarbituric acid reactive substances (TBARS) levels, superoxide dismutase (SOD) activity, protein content, and caspase-3 activity were quantified. Mortality (between 57 and 79%) was registered in G. catenatum after exposure to cell-free media of the three species. The maximal O2●− production occurred with C. marina var. marina cell-free media. The highest TBARS levels and SOD activity in G. catenatum were recorded with cell-free media from G. impudicum. The highest protein content was recorded with cell-free media from M. polykrikoides. All cell-free media caused an increase in the activity of caspase-3. These results indicate that the allelopathic effect in G. catenatum promotes cell stress and caspase-3 activation, as a signal for the induction of programmed cell death.

Inflammatory process, cellular stress and cell death in pancreatic acinar cells in response to toxic factors

Pancreatology ◽  
2013 ◽  
Vol 13 (4) ◽  
pp. e4
Author(s):  
M. Luaces-Regueira ◽  
M. Castiñeira-Alvariño ◽  
J.E. Domínguez-Muñoz
Keyword(s):  
Cell Death ◽  
Inflammatory Process ◽  
Cellular Stress ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Toxic Factors

Structure–function correlation of human programmed cell death 5 protein

2009 ◽  
Vol 486 (2) ◽  
pp. 141-149 ◽  
Author(s):  
Hongwei Yao ◽  
Lanjun Xu ◽  
Yingang Feng ◽  
Dongsheng Liu ◽  
Yingyu Chen ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Structure Function ◽  
Function Correlation ◽  
Programmed Cell Death 5

scholarly journals A Systems Biological Perspective of Cellular Stress-Directed Programmed Cell Death

2014 ◽  
Vol 04 (01) ◽  
pp. 28-34 ◽  
Author(s):  
Orsolya Kapuy ◽  
Beáta Lizák ◽  
Ibolya Stiller ◽  
Gábor Bánhegyi
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Cellular Stress ◽  
Biological Perspective

scholarly journals Editorial: Cellular Stress and Inflammation: How the Immune System Drives Tissue Homeostasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Fabrizio Antonangeli ◽  
Ola Grimsholm ◽  
Marianna Nicoletta Rossi ◽  
Francesca Velotti
Keyword(s):  
Immune System ◽  
Cellular Stress ◽  
Tissue Homeostasis

scholarly journals Inhibition of Fibroblast Apoptosis by Borrrelia afzelii, Coxiella burnetii and Bartonella henselae

2011 ◽  
Vol 60 (3) ◽  
pp. 269-272 ◽  
Author(s):  
TOMASZ CHMIELEWSKI ◽  
STANISŁAWA TYLEWSKA-WIERZBANOWSKA
Keyword(s):  
Cell Death ◽  
Chronic Disease ◽  
Coxiella Burnetii ◽  
Caspase 3 ◽  
Bartonella Henselae ◽  
Tissue Homeostasis ◽  
Host Cells ◽  
Fibroblast Cells ◽  
Human Fibroblast Cells ◽  
Long Time

Apoptosis is a genetically controlled mechanism of cell death involved in the regulation of tissue homeostasis. The aim of this study was to investigate the influence of Borrelia afzelii, Coxiella burnetii, and Bartonella henselae bacteria on apoptosis measured as the level of caspase 3 activity in human fibroblast cells HEL-299. Our findings show that C. burnetii bacteria may inhibit the process of apoptosis in the host cells for a long time. This can permit intracellular survival in the host and mediatingthe development of chronic disease.

scholarly journals Plants expressing murine pro-apoptotic protein Bid do not have enhanced PCD

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Anna Manara ◽  
Zahra Imanifard ◽  
Linda Fracasso ◽  
Diana Bellin ◽  
Massimo Crimi
Keyword(s):  
Cell Death ◽  
Stress Responses ◽  
Growth And Development ◽  
Active Form ◽  
Ectopic Expression ◽  
Signaling Cascade ◽  
Tobacco Plants ◽  
Truncated Protein ◽  
Apoptotic Protein ◽  
Family Protein

Abstract Objectives The purpose of this study was to explore whether plant programmed cell death (PCD) cascade can sense the presence of the animal-only BH3 protein Bid, a BCL-2 family protein known to play a regulatory role in the signaling cascade of animal apoptosis. Results We have expressed the mouse pro-apoptotic protein Bid in Arabidopsis thaliana and in Nicotiana tabacum. We did not obtain any transformed plant constitutively expressing the truncated protein (tBid—i.e. the caspase-activated form) whereas ectopic expression of the full-length protein (flBid) does not interfere with growth and development of the transformed plants. To verify whether the presence of this animal pro-apoptotic protein modified stress responses and PCD execution, both N. tabacum and A. thaliana plants constitutively expressing flBid have been studied under different stress conditions triggering cell death activation. The results show that the presence of flBid in transgenic plants did not significantly change the responses to abiotic stress (H2O2 or NO) and biotic stress treatments. Moreover, the finding that no Bid active form was present in treated tobacco plants suggests an absence of a proper activation of Bid.

Cell Stress Signaling Cascades Regulating Cell Fate

2018 ◽  
Vol 24 (27) ◽  
pp. 3176-3183 ◽  
Author(s):  
Rohit Gundamaraju ◽  
Ravichandra Vemuri ◽  
Wai Chin Chong ◽  
Dominic P. Geraghty ◽  
Rajaraman Eri
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Stress Responses ◽  
Cellular Stress ◽  
Cell Stress ◽  
Signaling Cascades ◽  
Stress Signaling ◽  
Cell Type ◽  
Induce Cell Death ◽  
Stressed Cell

Initiating anti-apoptotic signaling or triggering cell death depends to a great extent on the nature or source of cellular stress and cell type. Interplay between each stress response eventually determines the fate of stressed cell. Numerous factors induce cell death by a number of pathways including apoptosis, autophagy and necrosis. Not surprisingly, some of the pathways are interrelated to each other through a mediator that could articulate the entire mechanism. The present review attempts to consolidate all the pathways included in intrinsic cellular stress such as oxidative stress and autophagy, endoplasmic reticular stress (ERS) and mitophagy and apoptosis as fate in cell stress. These stress responses are a hallmark of numerous diseases including neurodegenerative diseases, diabetes and cancer. Understanding the cross-talk between different intrinsic cell stress responses will help to develop new therapeutic targets and hence lead to the development of new therapeutics.

scholarly journals Mutant p53 and Cellular Stress Pathways: A Criminal Alliance That Promotes Cancer Progression

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 614 ◽  
Author(s):  
Gabriella D’Orazi ◽  
Mara Cirone
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Survival ◽  
Cellular Stress ◽  
Hypoxia Inducible Factor ◽  
Related Factor ◽  
Protective Mechanisms ◽  
Key Factor ◽  
The Unfolded Protein Response

The capability of cancer cells to manage stress induced by hypoxia, nutrient shortage, acidosis, redox imbalance, loss of calcium homeostasis and exposure to drugs is a key factor to ensure cancer survival and chemoresistance. Among the protective mechanisms utilized by cancer cells to cope with stress a pivotal role is played by the activation of heat shock proteins (HSP) response, anti-oxidant response induced by nuclear factor erythroid 2-related factor 2 (NRF2), the hypoxia-inducible factor-1 (HIF-1), the unfolded protein response (UPR) and autophagy, cellular processes strictly interconnected. However, depending on the type, intensity or duration of cellular stress, the balance between pro-survival and pro-death pathways may change, and cell survival may be shifted into cell death. Mutations of p53 (mutp53), occurring in more than 50% of human cancers, may confer oncogenic gain-of-function (GOF) to the protein, mainly due to its stabilization and interaction with the above reported cellular pathways that help cancer cells to adapt to stress. This review will focus on the interplay of mutp53 with HSPs, NRF2, UPR, and autophagy and discuss how the manipulation of these interconnected processes may tip the balance towards cell death or survival, particularly in response to therapies.

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