The apoptosome: signalling platform of cell death

Riedl, Stefan J.; Salvesen, Guy S.

doi:10.1038/nrm2153

Cited by 922 publications

(750 citation statements)

References 53 publications

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“…Here, we have found that edefosine induces cytochrome c release from mitochondria in pancreatic cancer cells. Cytochrome c released from mitochondria binds to Apaf-1 and pro-caspase-9 to form the so-called apoptosome (Riedl and Salvesen, 2007). This complex catalyzes the activation of caspases that executes the apoptotic cell death program.…”

Section: Discussionmentioning

confidence: 99%

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

et al. 2011

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Pancreatic cancer remains as one of the most deadly cancers, and responds poorly to current therapies. The prognosis is extremely poor, with a 5-year survival of less than 5%. Therefore, search for new effective therapeutic drugs is of pivotal need and urgency to improve treatment of this incurable malignancy. Synthetic alkyl-lysophospholipid analogs (ALPs) constitute a heterogeneous group of unnatural lipids that promote apoptosis in a wide variety of tumor cells. In this study, we found that the anticancer drug edelfosine was the most potent ALP in killing human pancreatic cancer cells, targeting endoplasmic reticulum (ER). Edelfosine was taken up in significant amounts by pancreatic cancer cells and induced caspaseand mitochondrial-mediated apoptosis. Pancreatic cancer cells show a prominent ER and edelfosine accumulated in this subcellular structure, inducing a potent ER stress response, with caspase-4, BAP31 and c-Jun NH 2 -terminal kinase (JNK) activation, CHOP/GADD153 upregulation and phosphorylation of eukaryotic translation initiation factor 2 a-subunit that eventually led to cell death. Oral administration of edelfosine in xenograft mouse models of pancreatic cancer induced a significant regression in tumor growth and an increase in apoptotic index, as assessed by TUNEL assay and caspase-3 activation in the tumor sections. The ER stress-associated marker CHOP/ GADD153 was visualized in the pancreatic tumor isolated from edelfosine-treated mice, indicating a strong in vivo ER stress response. These results suggest that edelfosine exerts its pro-apoptotic action in pancreatic cancer cells, both in vitro and in vivo, through its accumulation in the ER, which leads to ER stress and apoptosis. Thus, we propose that the ER could be a key target in pancreatic cancer, and edelfosine may constitute a prototype for the development of a new class of antitumor drugs targeting the ER.

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Section: Discussionmentioning

confidence: 99%

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

et al. 2011

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“…As caspase-3 is a well-known executor enzyme in apoptosis pathway Nuclear DNA fragmentation and apoptosome complex formation are critical steps in the apoptotic process [40]. DNA fragmentation tests performed on 2008 cells treated for 24 h with IC 50 concentrations showed the ability of all gold(I) derivatives to increase mono-and oligo-nucleosome formation, although to a different extent (Fig.…”

Section: Apoptosis and Cell Cycle Studiesmentioning

confidence: 97%

“…In the first study [40] Thioredoxin reductase activity was assayed by measuring NADPH-dependent reduction of DTNB at 412 nm (A); glutathione reductase activity (B) and glutathione peroxidase (C) activities were followed at 340 nm. M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 M a n u s c r i p t a Unless otherwise specified, NMR spectra are recorded in chloroform-d,.…”

Section: Apoptosis and Cell Cycle Studiesmentioning

confidence: 99%

Cancer cell death induced by phosphine gold(I) compounds targeting thioredoxin reductase

Gandin

Fernandes

Dani

et al. 2010

Biochemical Pharmacology

230

193

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The thioredoxin system, composed of thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH (Nicotinamide adenine dinucleotide compounds were found to induce antiproliferative effects towards several human cancer cells some of which endowed with cisplatin or multidrug resistance. In addition, they were able to activate caspase-3 and induce apoptosis observed as nucleosome formation and sub-G1 cell accumulation. The complexes with thiocyanate and xanthate ligands were particularly effective in inhibiting thioredoxin reductase and inducing apoptosis.Pharmacodynamic studies in human ovarian cancer cells allowed for the correlatation of intracellular drug accumulation with TrxR inhibition that leads to the induction of apoptosis via the mitochondrial pathway.

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“…It turned out that the apoptosis, interleukin-27, angiopoietin receptor and the PI3K/ MAP kinase pathways are related to these candidate genes. The well-known tumour-suppressor gene, RB1, which was deleted in the RET/PTC-positive group of tumours and which is a key gene in the FAS signalling pathway (Nagata, 1994) is linked to the caspase cascade in the apoptosis pathway by CASP3 (Riedl and Salvesen, 2007). In normal cells an activation of RB1 by CASP3 leads to a repressed transcription of a series of cell cycle proteins by recruiting methyl-transferases that subsequently induce transcription-inactive heterochromatin (Tan and Wang, 1998;Nielsen et al, 2001).…”

Section: Array Cgh On Ptc K Unger Et Almentioning

confidence: 99%

Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC

et al. 2008

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The aim of this study is to investigate additional genetic alterations in papillary thyroid carcinomas (PTCs) with known RET/PTC rearrangements. We applied arraybased comparative genomic hybridization (array CGH) to 33 PTC (20 PTC from adults, 13 post-Chernobyl PTC from children) with known RET/PTC status. Principal component analysis and hierarchical cluster analysis identified cases with similar aberration patterns. Significant deviations between tumour-groups were obtained by statistical testing (Fisher's exact test in combination with Benjamini-Hochberg FDR-controlling procedure). FISH analysis on FFPE sections was applied to validate the array CGH data. Deletions were found more frequently in RET/PTC-positive and RET/PTC-negative tumours than amplifications. Specific aberration signatures were identified that discriminated between RET/PTC-positive and RET/PTC-negative cases (aberrations on chromosomes 1p, 3q, 4p, 7p, 9p/q, 10q, 12q, 13q and 21q). In addition, childhood and adult RET/PTC-positive cases differ significantly for a deletion on the distal part of chromosome 1p. There are additional alterations in RET/PTC-positive tumours, which may act as modifiers of RET activation. In contrast, alterations in RET/ PTC-negative tumours indicate alternative routes of tumour development. The data presented serve as a starting point for further studies on gene expression and function of genes identified in this study.

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The apoptosome: signalling platform of cell death

Cited by 922 publications

References 53 publications

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum

Cancer cell death induced by phosphine gold(I) compounds targeting thioredoxin reductase

Array CGH demonstrates characteristic aberration signatures in human papillary thyroid carcinomas governed by RET/PTC

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