Faculty Opinions recommendation of In situ trapping of activated initiator caspases reveals a role for caspase-2 in heat shock-induced apoptosis.

SummaryResistance to apoptosis due to caspase deregulation is considered one of the main hallmarks of cancer. However, the discovery of novel non-apoptotic caspase functions has revealed unknown intricacies about the interplay between these enzymes and tumor progression. To investigate this biological problem, we capitalized on a Drosophila tumor model highly relevant for humans that relies on the concomitant upregulation of EGFR and the JAK/STAT signaling pathway. Our results indicate that widespread non-apoptotic activation of initiator caspases limits JNK signaling and facilitates cell fate commitment in these tumors, thus preventing the overgrowth and exacerbation of malignant features. Intriguingly, these caspase functions are strongly linked to the ability of these enzymes to control the recruitment and subsequent proliferation in situ of macrophage-like cells on the tumor. These findings assign novel tumor-suppressor activities to caspases independent of apoptosis, while providing highly relevant molecular details to understanding their diverse contribution during tumor progression.

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Caspase-2–induced Apoptosis Requires Bid Cleavage: A Physiological Role for Bid in Heat Shock–induced Death

Molecular Biology of the Cell ◽

10.1091/mbc.e05-12-1107 ◽

2006 ◽

Vol 17 (5) ◽

pp. 2150-2157 ◽

Cited By ~ 99

Author(s):

Christine Bonzon ◽

Lisa Bouchier-Hayes ◽

Lisa J. Pagliari ◽

Douglas R. Green ◽

Donald D. Newmeyer

Keyword(s):

Heat Shock ◽

Cytochrome C ◽

Physiological Role ◽

Wild Type ◽

Cytochrome C Release ◽

Embryonic Fibroblasts ◽

Family Protein ◽

Caspase 2 ◽

Induced Apoptosis ◽

Active Caspase

The mechanisms through which Caspase-2 leads to cell death are controversial. Here we show, using a combination of cell-free and cell culture-based approaches, that cleavage of the Bcl-2-family protein Bid is required for the induction of apoptosis by Caspase-2. Caspase-2 promoted cytochrome c release from mitochondria in the presence of cytosol from wild-type, but not Bid-deficient, mouse embryonic fibroblasts (MEFs). Recombinant wild-type Bid, but not a noncleavable mutant (D59E), restored cytochrome c release. Similarly, Bid-null MEFs were relatively resistant to apoptosis triggered by active Caspase-2, and apoptosis was restored in Bid-null cells by the expression of wild-type, but not D59E, Bid. Finally, Bid-null MEFs were substantially more resistant to apoptosis induced by heat shock, which has been shown to be dependent on apical activation of Caspase-2. The data are consistent with a model in which Caspase-2 induces apoptosis via cleavage of Bid at D59 and the subsequent engagement of the mitochondrial (intrinsic) pathway.

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Absence of temporal ordering of apoptotic features in heat-shock treated leukemia and lymphoma cell lines

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100166257 ◽

1996 ◽

Vol 54 ◽

pp. 758-759

Author(s):

D. W. Fairbain ◽

M.D. Standing ◽

K.L. O'Neill

Keyword(s):

Heat Shock ◽

Cell Lines ◽

Chromatin Condensation ◽

Membrane Integrity ◽

Resistant Cell ◽

Membrane Blebbing ◽

Late Loss ◽

Induced Apoptosis ◽

Dying Cells ◽

In Cells

Apoptosis is a genetically defined response to physiological stimuli that results in cellular suicide. Features common to apoptotic cells include chromatin condensation, oligonucleosomal DNA fragmentation, membrane blebbing, nuclear destruction, and late loss of ability to exclude vital dyes. These characteristics contrast markedly from pathological necrosis, in which membrane integrity loss is demonstrated early, and other features of apoptosis, which allow a non-inflammatory removal of dead and dying cells, are absent. Using heat shock-induced apoptosis as a model for examining stress response in cells, we undertook to categorize a variety of human leukemias and lymphomas with regard to their response to heat shock. We were also interested in determining whether a common temporal order was followed in cells dying by apoptosis. In addition, based on our previous results, we investigated whether increasing heat load resulted in increased apoptosis, with particular interest in relatively resistant cell lines, or whether the mode of death changed from apoptosis to necrosis.

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Faculty Opinions recommendation of c-Myc and caspase-2 are involved in activating Bax during cytotoxic drug-induced apoptosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1108252.564273 ◽

2008 ◽

Author(s):

David Andrews

Keyword(s):

Cytotoxic Drug ◽

Drug Induced ◽

Caspase 2 ◽

Induced Apoptosis

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Apoptosis in human cultured trophoblasts is enhanced by hypoxia and diminished by epidermal growth factor

AJP Cell Physiology ◽

10.1152/ajpcell.2000.278.5.c982 ◽

2000 ◽

Vol 278 (5) ◽

pp. C982-C988 ◽

Cited By ~ 145

Author(s):

Roni Levy ◽

Steven D. Smith ◽

Kala Chandler ◽

Yoel Sadovsky ◽

D. Michael Nelson

Keyword(s):

Cell Differentiation ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Caspase Inhibitor ◽

Trophoblast Differentiation ◽

Epidermal Growth ◽

Induced Apoptosis

Preeclampsia and fetal growth restriction are associated with placental hypoperfusion and villous hypoxia. The villous response to this environment includes diminished trophoblast differentiation and enhanced apoptosis. We tested the hypothesis that hypoxia induces apoptosis in cultured trophoblasts, and that epidermal growth factor (EGF), an enhancer of trophoblast differentiation, diminishes hypoxia-induced apoptosis. Trophoblasts isolated from placentas of term-uncomplicated human pregnancies were cultured up to 72 h in standard ([Formula: see text]= 120 mmHg) or hypoxic ([Formula: see text] < 15 mmHg) conditions. Exposure to hypoxia for 24 h markedly enhanced trophoblast apoptosis as determined by DNA laddering, internucleosomal in situ DNA fragmentation, and histomorphology, as well as by the reversibility of the apoptotic process with a caspase inhibitor. Apoptosis was accompanied by increased expression of p53 and Bax and decreased expression of Bcl-2. Addition of EGF to cultured trophoblasts or exposure of more differentiated trophoblasts to hypoxia significantly lowered the level of apoptosis. We conclude that hypoxia enhances apoptosis in cultured trophoblasts by a mechanism that involves an increase in p53 and Bax expression. EGF and enhancement of cell differentiation protect against hypoxic-induced apoptosis.

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73; PRIOR HEAT SHOCK IS NOT PROTECTIVE AGAINST HEAT SHOCK-INDUCED APOPTOSIS FOLLOWING ENDOTOXIN

Shock ◽

10.1097/00024382-199401001-00074 ◽

1994 ◽

Vol 1 (Supplement) ◽

pp. 21

Author(s):

P. Abello ◽

S. Fidler ◽

T. G. Buchman

Keyword(s):

Heat Shock ◽

Induced Apoptosis

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Urea sensitizes mIMCD3 cells to heat shock-induced apoptosis: protection by NaCl

AJP Cell Physiology ◽

10.1152/ajpcell.2001.280.3.c614 ◽

2001 ◽

Vol 280 (3) ◽

pp. C614-C620 ◽

Cited By ~ 11

Author(s):

Chantal Colmont ◽

Stéphanie Michelet ◽

Dominique Guivarc'h ◽

Germain Rousselet

Keyword(s):

Heat Shock ◽

Heat Shock Response ◽

Heat Sensitivity ◽

Osmotic Gradient ◽

Water Reabsorption ◽

Apoptotic Pathway ◽

Shock Response ◽

Induced Apoptosis ◽

Shock Proteins ◽

Dose Dependent

Urea, with NaCl, constitutes the osmotic gradient that allows water reabsorption in mammalian kidneys. Because NaCl induces heat shock proteins, we tested the responses to heat shock of mIMCD3 cells adapted to permissive urea and/or NaCl concentrations. We found that heat-induced cell death was stronger after adaptation to 250 mM urea. This effect was reversible, dose dependent, and, interestingly, blunted by 125 mM NaCl. Moreover, we have shown that urea-adapted cells engaged in an apoptotic pathway upon heat shock, as shown by DNA laddering. This sensitization is not linked to a defect in the heat shock response, because the induction of HSP70 was similar in isotonic and urea-adapted cells. Moreover, it is not linked to the presence of urea inside cells, because washing urea away did not restore heat resistance and because applying urea and heat shock at the same time did not lead to heat sensitivity. Together, these results suggest that urea modifies the heat shock response, leading to facilitated apoptosis.

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Metabolomic Profiling Reveals a Role for Caspase-2 in Lipoapoptosis

Journal of Biological Chemistry ◽

10.1074/jbc.m112.437210 ◽

2013 ◽

Vol 288 (20) ◽

pp. 14463-14475 ◽

Cited By ~ 29

Author(s):

Erika Segear Johnson ◽

Kelly R. Lindblom ◽

Alexander Robeson ◽

Robert D. Stevens ◽

Olga R. Ilkayeva ◽

...

Keyword(s):

Mammalian Cells ◽

Metabolic Diseases ◽

Response To Treatment ◽

Alcoholic Fatty Liver ◽

Metabolomic Profiling ◽

Egg Extracts ◽

Attractive Therapeutic Target ◽

Caspase 2 ◽

Induced Apoptosis ◽

Alcoholic Fatty Liver Disease

The accumulation of long-chain fatty acids (LCFAs) in non-adipose tissues results in lipid-induced cytotoxicity (or lipoapoptosis). Lipoapoptosis has been proposed to play an important role in the pathogenesis of several metabolic diseases, including non-alcoholic fatty liver disease, diabetes mellitus, and cardiovascular disease. In this report, we demonstrate a novel role for caspase-2 as an initiator of lipoapoptosis. Using a metabolomics approach, we discovered that the activation of caspase-2, the initiator of apoptosis in Xenopus egg extracts, is associated with an accumulation of LCFA metabolites. Metabolic treatments that blocked the buildup of LCFAs potently inhibited caspase-2 activation, whereas adding back an LCFA in this scenario restored caspase activation. Extending these findings to mammalian cells, we show that caspase-2 was engaged and activated in response to treatment with the saturated LCFA palmitate. Down-regulation of caspase-2 significantly impaired cell death induced by saturated LCFAs, suggesting that caspase-2 plays a pivotal role in lipid-induced cytotoxicity. Together, these findings reveal a previously unknown role for caspase-2 as an initiator caspase in lipoapoptosis and suggest that caspase-2 may be an attractive therapeutic target for inhibiting pathological lipid-induced apoptosis.

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