CPYPP induces paraptosis in MDA-MB-435 melanoma cells.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens (human)
SUBMITTER: Ling-Chu Chang
PROVIDER: PXD050304 | JPOST Repository | Tue Mar 04 00:00:00 GMT 2025
REPOSITORIES: jPOST
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| CPYPP-raw.zip | Other | |||
| CPYPP-result.zip | Other |
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Project description:Background: Paraptosis is a programmed cell death characterized by cytoplasmic vacuolation, which has been used as an alternative cell death method for cancer treatment and is associated with cancer resistance. However, the mechanisms underlying the progression of paraptosis in cancer cells are largely unknown. Methods: Paraptosis-inducing agents, CPYPP, cyclosporin, and curcumin, were utilized to investigate the underlying mechanism of paraptosis. Next-generation sequencing and liquid chromatography-mass spectrometry analysis revealed significant changes in gene and protein expressions. Pharmacological and genetic approaches were employed to elucidate the transcriptional events related to paraptosis. The xenograft mouse models were employed to evaluate the potential of paraptosis as an anti-cancer strategy. Results: CPYPP, cyclosporin A, and curcumin induced cytoplasmic vacuolization and triggered paraptosis in cancer cells. The paraptotic program involved reactive oxygen species (ROS) provocation and the activation of proteostatic dynamics, leading to transcriptional activation associated with redox homeostasis and proteostasis. Both pharmacological and genetic approaches suggested that cyclin-dependent kinase (CDK) 7/9 drive paraptotic progression in a mutually-dependent manner with heat shock proteins (HSPs). Proteostatic stress, such as accumulated cysteine-thiols, HSPs, ubiquitin-proteasome system, endoplasmic reticulum stress, and unfolded protein response, as well as ROS provocation primarily within the nucleus, enforced CDK7/CDK9–Rpb1 (RNAPII subunit B1) activation by potentiating its interaction with HSPs and protein kinase R (PKR) in a forward loop, amplifying transcriptional regulation and thereby exacerbating proteotoxicity leading to initiate paraptosis. A xenograft mouse model with OECM-1 cells further confirmed the induction of paraptosis against tumor growth. Conclusions We propose a novel regulatory paradigm in which the activation of CDK7/CDK9–Rpb1 by nuclear proteostatic stress mediates transcriptional regulation to prime cancer cell paraptosis.
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Project description:Coral bleaching has devastating effects on coral survival and reef ecosystem function, but many of the fundamental cellular effects of thermal stress on cnidarian physiology are unclear. We used label-free liquid chromatography-tandem mass spectrometry to assess the effects of high temperatures on the proteome of the model symbiotic anemone Aiptasia sp. Anemones were acclimated to elevated temperatures (30 °C and 33.5 °C) for two weeks or exposed to short-term thermal shock (33.5 °C, 24 hours) without acclimation. We identified 2,137 protein clusters in Aiptasia, 136 of which were differentially abundant between treatments. There were minimal differences (nine proteins) in protein abundances between the control (25 °C) and acclimated high-temperature (30 °C and 33.5 °C) treatments, indicating that thermal acclimation in symbiotic cnidarians is not primarily regulated at the level of protein expression. Heat shock resulted in significant changes in the abundance of 104 proteins, including those involved in protein folding and synthesis, redox homeostasis, and central metabolism. Nineteen highly abundant cytoskeletal and structural proteins showed particularly reduced abundance (approximately 50%), demonstrating proteostasis disruption and inhibition of protein synthesis. Heat shock induced proteins involved in multiple mechanisms for stabilizing nascent proteins, preventing protein aggregation and degrading damaged proteins, indicative of endoplasmic reticulum stress. Antioxidant mechanisms and metabolic enzymes necessary for redox homeostasis were also upregulated. Disruption of host proteostasis occurred before either bleaching or symbiont photoinhibition was detected, strongly suggesting endogenous reactive oxygen species production as the proximate cause of thermal damage. The effects of thermal shock were most pronounced at the endoplasmic reticulum, and proteostasis maintenance and protein turnover mechanisms may be essential in the response to severe thermal stress in symbiotic cnidarians.
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2020-03-30 | PXD014381 | Pride
Project description:Redox signaling mediated by reversible oxidative cysteine thiol modifications is crucial for driving cellular adaptation to dynamic environmental changes, maintaining homeostasis, and ensuring proper function. This is particularly critical in pancreatic β-cells, which are highly metabolically active and play a specialized role in whole organism glucose homeostasis. Glucose stimulation in β-cells triggers signals leading to insulin secretion, including changes in ATP/ADP ratio and intracellular calcium levels. Additionally, lipid metabolism and reactive oxygen species (ROS) signaling are essential for β-cell function and health. We employed IodoTMT isobaric labeling combined with tandem mass spectrometry to elucidate redox signaling pathways in pancreatic β-cells.
2024-09-30 | PXD052765 | Pride
Project description:The accumulation of reactive oxygen species (ROS) is linked to several cardiovascular pathologies; it is also associated with cell cycle exit by nenonatal cardiomyocytes, a key limiting factor in the regenerative capacity of the adult mammalian heart. BMI1 is a component of the polycomb complex 1, which is linked to adult multipotent progenitors, and is also an important partner in DNA repair and redox regulation. Here we show that high BMI1 expression is associated with a cardiac Sca1+ progenitor subpopulation with low ROS levels. In homeostasis, BMI1 represses cell-fate genes, including a cardiogenic differentiation program. Persistent oxidative damage nonetheless modified BMI1 activity in vivo, by derepressing canonical target genes in favor of their antioxidant and anticlastogenic functions. This derepression induced cardiac progenitor proliferation and differentiation, and thus increased its contribution to mature cardiac progeny. This redox-mediated mechanism is not restricted to damage situations, and we report ROS-associated differentiation of cardiac progenitors in steady state. These findings demonstrate how redox status influences the adult cardiac progenitor response, and identifies a redox-mediated BMI1 function with potential implications in adult cardiac turnover.
2018-01-01 | GSE92700 | GEO
Project description:Precise regulation of stem cell activity is crucial for tissue homeostasis. In Drosophila, intestinal stem cells (ISCs) maintain the midgut epithelium and respond to oxidative challenges by increasing proliferation rates. However, the connection between intestinal homeostasis and redox signaling remains obscure. Here we identify Caliban (Clbn) as a novel mitochondrial protein involved in regulating the cellular redox state in enterocytes (ECs) and the proliferative activity of ISCs. We find that clbn knock-out flies lose the intestinal homeostasis characterized by increased ISCs proliferation, disrupted intestinal epithelial integrity, reduced viability in response to harmful stress and shortened lifespan. Mechanistically, Clbn is highly expressed and localized to mitochondria in ECs, and loss of clbn impairs mitochondrial morphology and functions, result in accumulation of reactive oxygen species, ECs damage and activation of JNK and JAK-STAT signaling pathways. Furthermore, loss of clbn promotes tumor growth in gut generated by activating Ras in intestinal progenitor cells. Our findings reveal the essential role of Clbn in maintaining intestinal homeostasis and may provide new insight into the functional link among mitochondrial redox modulation, tissue homeostasis and cancer.
2022-01-01 | GSE125032 | GEO
Project description:It is well appreciated that reactive oxygen species (ROS) are deleterious to mammals, including humans, especially when generated in abnormally large quantities from cellular metabolism. Whereas the mechanisms leading to the production of ROS are rather well delineated, the mechanisms underlying tissue susceptibility or tolerance to oxidant stress remain elusive. Through an experimental selection over many generations, we have previously generated Drosophila melanogaster flies that tolerate tremendous oxidant stress and have shown that the family of antimicrobial peptides (AMP) is over-represented in these tolerant flies. Furthermore, we have also demonstrated that overexpression of even one AMP at a time (e.g. Diptericin) allows wild type flies to survive much better in hyperoxia. In the current study, we used a number of experimental approaches to investigate the potential mechanisms underlying hyperoxia tolerance in flies with antimicrobial peptide overexpression. We demonstrate that flies with Diptericin overexpression resist oxidative stress by increasing antioxidant enzyme activities and preventing an increase in ROS level after hyperoxia. Depleting the GSH pool using buthionine sulfoximine limits fly survival, thus confirming that enhanced survival observed in these flies is related to improved redox homeostasis. We conclude that a) AMPs play an important role in tolerance to oxidant stress; b) overexpression of Diptericin changes the cellular redox balance between oxidant and antioxidant, and c) this change in redox balance plays an important role in survival in hyperoxia. Expression profiles of Drosophila melanogaster with anti-microbial peptide over-expression (experimental sample; n=3) and controls (UAS-AMP alone not crossed to da-GAL4; n=3) were determined using Affymetrix Drosophila Genome 2.0 Arrays.
2010-12-21 | E-GEOD-23902 | biostudies-arrayexpress
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2024-06-16 | PXD039852 | Pride
Project description:Objective: Redox signaling mediated by reversible oxidative cysteine thiol modifications is crucial for driving cellular adaptation to dynamic environmental changes, maintaining homeostasis, and ensuring proper function. This is particularly critical in pancreatic β-cells, which are highly metabolically active and play a specialized role in whole organism glucose homeostasis. Glucose stimulation in β-cells triggers signals leading to insulin secretion, including changes in ATP/ADP ratio and intracellular calcium levels. Additionally, lipid metabolism and reactive oxygen species (ROS) signaling are essential for β-cell function and health. Methods: We employed IodoTMT isobaric labeling combined with tandem mass spectrometry to elucidate redox signaling pathways in pancreatic β-cells. Results: Glucose stimulation significantly increases ROS levels in β-cells, leading to targeted reversible oxidation of proteins involved in key metabolic pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, pyruvate metabolism, oxidative phosphorylation, protein processing in the endoplasmic reticulum (ER), and insulin secretion. Furthermore, the glucose-induced increase in reversible cysteine oxidation correlates with the presence of other post-translational modifications, including acetylation and phosphorylation. Conclusions: Proper functioning of pancreatic β-cell metabolism relies on fine-tuned regulation, achieved through a sophisticated system of diverse post-translational modifications that modulate protein functions. Our findings demonstrate that glucose induces the production of ROS in pancreatic β-cells, leading to targeted reversible oxidative modifications of proteins. Furthermore, protein activity is modulated by acetylation and phosphorylation, highlighting the complexity of the regulatory mechanisms in β-cell function.
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Project description:This model is from the article:
Modelling the Role of the Hsp70/Hsp90 System in the Maintenance of Protein Homeostasis
Proctor CJ, Lorimer IAJ
PLoS ONE2011; 6(7): e22038.
doi:10.1371/journal.pone.0022038,
Abstract:
Neurodegeneration is an age-related disorder which is characterised by the accumulation of aggregated protein and neuronal cell death. There are many different neurodegenerative diseases which are classified according to the specific proteins involved and the regions of the brain which are affected. Despite individual differences, there are common mechanisms at the sub-cellular level leading to loss of protein homeostasis. The two central systems in protein homeostasis are the chaperone system, which promotes correct protein folding, and the cellular proteolytic system, which degrades misfolded or damaged proteins. Since these systems and their interactions are very complex, we use mathematical modelling to aid understanding of the processes involved. The model developed in this study focuses on the role of Hsp70 (IPR00103) and Hsp90 (IPR001404) chaperones in preventing both protein aggregation and cell death. Simulations were performed under three different conditions: no stress; transient stress due to an increase in reactive oxygen species; and high stress due to sustained increases in reactive oxygen species. The model predicts that protein homeostasis can be maintained during short periods of stress. However, under long periods of stress, the chaperone system becomes overwhelmed and the probability of cell death pathways being activated increases. Simulations were also run in which cell death mediated by the JNK (P45983) and p38 (Q16539) pathways was inhibited. The model predicts that inhibiting either or both of these pathways may delay cell death but does not stop the aggregation process and that eventually cells die due to aggregated protein inhibiting proteasomal function. This problem can be overcome if the sequestration of aggregated protein into inclusion bodies is enhanced. This model predicts responses to reactive oxygen species-mediated stress that are consistent with currently available experimental data. The model can be used to assess specific interventions to reduce cell death due to impaired protein homeostasis.
Note:
Simulations were performed under three different conditions: 1) normal condition (no stress), 2) moderate stress due to an increase in reactive oxygen species (ROS) i.e. ROS levels were increased by a factor of 4 at time=4hours for a period of 1 hour (not 2 hours as mentioned in the figure 5 legend of the reference publication. This is a typo in the paper and is clarified by the author) and 3) high stress due to sustained increase in reactive oxygen species (ROS) (here ROS increases with time).
The model that corresponds to the normal condition is submitted as a main model in the BioModels Database. The other two models, that corresponds to the moderate stress conditions and high stress conditions are available in SBML format as supporting files [go to Curation tab].
Supplementary figures S3 (normal condition), S4 (moderate stress condition) and S6 (high stress condition) are reproduced here.
2024-09-02 | BIOMD0000000344 | BioModels