Failed apoptosis enhances melanoma cancer cells aggressiveness
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE137278 | GEO | 2020/05/02
REPOSITORIES: GEO
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Project description:TP53-mutant blood cancers remain a major clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins to promote cancer cell apoptosis. Despite acting downstream of TP53, functional TP53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report TP53 can be activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, which leads to induction of BH3-only proteins, thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feed-forward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 could be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through TP53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetics efficiently killed TP53-mutant mouse B lymphoma, human NK/T lymphoma and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.
2024-04-25 | GSE261373 | GEO
Project description:Failed apoptosis enhances melanoma cancer cells aggressiveness
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Project description:We identified a novel form of caspase-independent cell death (CICD) induced by BH3-mimetics. To characterize the transcriptional changes during CICD and compare these to apoptotic changes, we performed RNA Seq analysis on SUDHL6 lymphoma cells treated with the MCL1 inhibitor S63845 in the presence or abscence of the broad spectrum caspase inhibitor zVAD.fmk.
2024-04-24 | GSE263183 | GEO
Project description:Intrinsic apoptosis is principally regulated by the BCL-2 family of proteins, but some non-BCL-2 proteins also serve as important regulators. To identify novel apoptosis regulators, we performed a genome-wide CRISPR-Cas9 library screen, and it identified the mitochondrial E3 ubiquitin ligase MARCHF5/MITOL/RNF153 as an important regulator of BAK apoptotic function. Deleting MARCHF5 in multiple BAX-deficient cell lines conferred profound resistance to BH3-mimetic drugs. The loss of MARCHF5 or its E3 ubiquitin ligase activity surprisingly drove BAK to adopt an active conformation, with resistance to BH3-mimetics afforded by the formation of inhibitory complexes with pro-survival proteins MCL-1 and BCL-XL. Importantly, these changes to BAK conformation and pro-survival association occurred independently of BH3-only proteins. This study identifies a mechanism by which MARCHF5 regulates apoptotic cell death and provides new insight into how cancer cells respond to BH3-mimetic drugs. These data also highlight the emerging role of ubiquitin signalling in apoptosis that may be exploited therapeutically.
2022-09-25 | PXD030246 | Pride
Project description:While immune responses during nervous system injury and disease are well studied, exactly how primary neurons respond to immune signals is still largely unknown. We find that primary sympathetic neurons respond unexpectedly to interferon-gamma (IFN-γ), a cytokine released by immune cells in response to infection. While IFN-γ induces apoptosis in many cell types, it has the opposite effect on sympathetic neurons by protecting them from apoptotic stimuli. We found that IFN-γ addition enabled sympathetic neurons to become resistant to nerve growth factor (NGF) deprivation- or pan-kinase inhibition-induced apoptosis. In investigating how interferon modulates the apoptotic pathway, we discovered that c-jun phosphorylation and Bim induction in response to NGF deprivation were unchanged with IFN-γ. Downstream of the mitochondria, however, IFN-γ blocked cytochrome c release and caspase-3 activation in NGF-deprived neurons. Microinjection of cytochrome c into XIAP-/- neurons revealed no difference in cell death with IFN-γ addition, demonstrating a role for IFN-γ at the point of mitochondria permeabilization. Levels of Bax and Bcl-XL, molecules that help regulate mitochondrial permeabilization, were unchanged. These results identify Bax activation as the likely point at which IFN-γ acts to inhibit neuronal apoptosis.
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Project description:Cells are in constant adaptation to environmental changes to insure their proper functioning. When exposed to stresses, cells activate specific pathways to elicit adaptive modifications. Those changes can be mediated by selective modulation of gene and protein expression as well as by post-translational modifications, such as phosphorylation and proteolytic processing. Protein cleavage, as a controlled and limited post-translational modification, is involved in diverse physiological processes such as the maintenance of protein homeostasis, activation of repair pathways, apoptosis and the regulation of proliferation. Here we assessed by quantitative proteomics the proteolytic landscape in two cell lines subjected to low cisplatin concentrations used as a mild non-lethal stress paradigm. This landscape was compared to the one obtained in the same cells stimulated with cisplatin concentrations inducing apoptosis. These analyses were performed in wild-type cells and in cells lacking the two main executioner caspases: caspase-3 and caspase-7. Ninety proteins were found to be cleaved at one or a few sites (discrete cleavage) in low stress conditions compared to four hundred and forty in apoptotic cells. Many of the cleaved proteins in stressed cells were also found to be cleaved in apoptotic conditions. As expected in apoptotic cells, ~80% of the cleavage events were dependent on caspase 3/caspase 7. Strikingly, upon exposure to non-lethal stresses, no discrete cleavage was detected in cells lacking caspase-3 and caspase-7. This indicates that the proteolytic landscape in stressed viable cells fully depends on the activity of executioner caspases. These results suggest that the so-called executioner caspases fulfill important stress adaptive responses distinct from their role in apoptosis.
2021-07-07 | PXD023488 | Pride
Project description:How mechanical stress might influence the resistance of cancer cells to cell death is currently unknown. To address this, we mimicked the mechanical constrictions that cancer cells might encounter when invading through rich tumoral stroma or undergoing intra- and extravasation. We found that extreme constrictional migration (ECM) but not compression increases the resistance of breast cancer cells to anoikis, a variant of apoptosis triggered by loss of cell adhesions. We also found that Inhibitory of Apoptosis Proteins (IAPs) are responsible for ECM-triggered resistance to anoikis. Together with enhanced cell motility and resistance to natural killer-mediated immune-surveillance, we show that anoikis resistant ECM mechanically-challenged cancer cells have a marked advantage to form lung metastatic lesions. Taken together, our study connects the constrictional mechanical stress typically characterizing the metastatic colonization with the resistance to cell death, while therapeutically targeting the IAPs by SMAC mimetics could counteract anoikis resistance in breast cancer cells.
2022-02-16 | GSE176081 | GEO
Project description:Caspase is best known as an enzyme involved in programmed cell death that is conserved in multicellular organisms. In addition to its role in cell death, caspase is emerging as an indispensable enzyme for a wide range of cellular functions, which have recently been termed as Caspase-Dependent non-lethal cellular Processes. We carefully examined the involvement of cell death signaling in tissue size determination using Drosophila wing as a model. We found that executioner caspase activity promoted wing growth independent of apoptosis. To identify the gene expression changes which account for the observed phenomena, we performed microarray analysis of wing imaginal disc upon caspase activity-inhibition by overexpressing p35. The analysis revealed the change in overall transcriptome, but not in the major tissue growth promoting signaling pathways.
2019-08-22 | GSE136170 | GEO
Project description:Caspase-8 is a protease with both pro-death and pro-survival functions: it is required for apoptosis induced by death receptors such as TNFR1 (tumour necrosis factor receptor 1), and it has a critical role in suppressing necroptosis mediated by the kinase RIPK3 (receptor interacting protein kinase 3) and the pseudokinase MLKL (mixed lineage kinase-like). Mice lacking caspase-8 display MLKL-dependent embryonic lethality, as do mice expressing catalytically inactive caspase-8 mutant C362A. However, Casp8C362A/C362A Mlkl-/- mice die in the perinatal period, whereas Casp8-/- Mlkl-/- mice are viable, indicating that inactive caspase-8 also has a pro-death scaffolding function. Here we show that caspase-8 C362A triggers ASC speck formation and caspase-1-dependent pyroptosis in MLKL-deficient intestinal epithelial cells (IECs) around embryonic day 18. Pyroptosis contributed to the perinatal lethal phenotype because a number of Casp8 C362A/C362A Mlkl-/- Casp1-/- mice survived beyond weaning. Transfection studies suggested inactive caspase-8 adopts a distinct conformation to wild-type caspase-8, enabling it to engage the caspase-1 adaptor ASC. Wild-type caspase-8 was found in the Triton X-100 soluble fraction, whereas wild-type caspase-8 inhibited with the pan-caspase inhibitor emricasan, or inactive caspase-8 mutant C362A, were detected in the insoluble fraction. Moreover, inhibited or inactive caspase-8 shifted ASC into the insoluble fraction. Perinatal lethality was recapitulated when expression of caspase-8 C362A was restricted to IECs, but intriguingly, only in the absence of MLKL. Hence, unanticipated plasticity in death pathways is revealed such that IECs can undergo caspase-1-dependent death when caspase-8-dependent apoptosis and MLKL-dependent necroptosis are inhibited.
2019-09-20 | GSE132133 | GEO