Caspase-8 Interacts with the p85 Subunit of Phosphatidylinositol 3-Kinase to Regulate Cell Adhesion and Motility

Senft, Jamie; Helfer, Brooke; Frisch, Steven M.

doi:10.1158/0008-5472.can-07-5755

Cited by 104 publications

(129 citation statements)

References 18 publications

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“…26 Caspase 8 also seems to play a role in cell adhesion and motility. 27 In our study, we found definitive evidence that caspases are at the crux of both TRAIL-induced apoptosis and proliferation of RA FLS, as a pan-caspase inhibitor blocked both cellular responses. The use of specific caspase inhibitors suggested an involvement of caspases 3, 8 and 9 in TRAIL-induced apoptosis, and of caspases 3 and 8 in TRAIL-induced proliferation.…”

supporting

confidence: 62%

The pleiotropic effect of TRAIL on tumor-like synovial fibroblasts from rheumatoid arthritis patients is mediated by caspases

et al. 2009

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The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has gained much attention as a possible therapeutic reagent for the treatment of tumors, as TRAIL was originally described to induce apoptosis specifically in cancer cells, but not in normal cells. Fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) patients exhibit tumor-like features and we have described earlier that TRAIL induces apoptosis only in a subset of RA FLS, but an induction of proliferation in the surviving cells. This observation corresponds to the pleiotropic effects of TRAIL observed on primary human tumor cells. Here, we describe that the PI3 kinase/Akt-signaling pathway, but not that of the MAP kinases ERK and p38, protects RA FLS from TRAIL-induced apoptosis by modulating the expression of the cell survival regulators p21, XIAP, Mcl-1 and RIP. Moreover, we found that not only TRAIL-induced apoptosis, but also TRAIL-triggered proliferation in RA FLS is mediated by caspases with a crucial role for caspase 8. TRAIL was found to induce degradation of p21 and p27 that was caspase-dependent, but independent of the ERK, p38 and PI3 kinase/Akt-signaling pathways. The finding that TRAIL-triggered proliferation and apoptosis share intracellular routes has to be taken in consideration in defining therapeutic strategies on the basis of the administration of TRAIL. In recent years, considerable attention has been focused on the potential benefits of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in cancer therapy, as a broad range of cancer cells are sensitive to TRAIL-induced apoptosis (reviewed in 1 ). In addition, the use of TRAIL in combination with chemotherapeutic agents or irradiation strengthens its apoptotic effects and frequently sensitizes the otherwise TRAIL-resistant tumor cells. It is important that TRAIL does not seem to be toxic to normal cells, as TRAIL exposure shows no toxic side effects of therapeutically relevant doses in primates.Tumor necrosis factor (TNF)-related apoptosis-inducing ligand can interact with five different receptors: four membrane-anchored receptors TRAIL-R1 (DR4), TRAIL-R2 (DR5), TRAIL-R3 (DcR1) and TRAIL-R4 (DcR2) and a soluble decoy receptor osteoprotegerin. The receptors TRAIL-R1 and -R2 contain an intracellular cytoplasmic sequence motif, known as the death domain (DD), and can induce apoptosis through activation of caspases (reviewed in 2 ). Nevertheless, TRAIL-receptors R1 and R2 not only trigger apoptosis, but also proliferation and differentiation depending on the cell type (reviewed in 2 ). This phenomenon has been described for several other members of the TNF family and it is thought that one pathway potentially pre-dominates, but that a build-up of intracellular regulators can flick the switch from cell death to proliferation and vice versa. 2,3 For example, TRAIL has been shown to promote cell survival and proliferation of endothelial and vascular smooth muscle cells 4,5 and to regulate erythroid and monocytic maturation. 6 Evidence is accumulati...

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supporting

confidence: 62%

The pleiotropic effect of TRAIL on tumor-like synovial fibroblasts from rheumatoid arthritis patients is mediated by caspases

et al. 2009

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“…Fas) or other proteins in the death receptor pathways (e.g. caspase-8 and Fas-associated death domain) promotes tumor formation, growth, invasion, and even metastasis (45)(46)(47)(48)(49)(50)(51)(52). Thus, it is also possible that Ras-induced DR5 expression is involved in promoting Ras-mediated oncogenesis and/or metastasis, particularly under apoptosis-compromised conditions.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Ras and B-Raf Proteins Positively Regulate Death Receptor 5 Expression through Co-activation of ERK and JNK Signaling

Yue

Zhou

et al. 2012

Journal of Biological Chemistry

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Background:The oncogene Ras induces DR5 expression with undefined mechanism. Results: Both Ras and B-Raf induce DR5 expression through co-activation of ERK and JNK signaling and subsequent cooperative effects among CHOP, Elk1, and c-Jun. Conclusion: Co-activation of ERK and JNK signaling accounts for Ras-induced DR5 expression. Significance: A novel function of DR5 in Ras-or B-Raf-mediated oncogenesis may be suggested.

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“…So, in NB7 neuroblastoma cells with hyperactive Src or stimulated with EGF, caspase-8 becomes phosphorylated on Y380 enabling the protein to bind the p85 subunit of PI3K and to activate the PI3K effector Rac, which is of pivotal relevance for cell migration. 29,30 In this model of cell migration, the enzymatic activity of caspase-8 is again dispensable. 29,30 In the same cellular model, a non-catalytic function of caspase-8 in Src-dependent cell adhesion and activation of extracellular-regulated kinase 1/2 has also been shown, but the relation of these events to p85/Rac-mediated cell migration is still unclear.…”

Section: Discussionmentioning

confidence: 99%

“…29,30 In this model of cell migration, the enzymatic activity of caspase-8 is again dispensable. 29,30 In the same cellular model, a non-catalytic function of caspase-8 in Src-dependent cell adhesion and activation of extracellular-regulated kinase 1/2 has also been shown, but the relation of these events to p85/Rac-mediated cell migration is still unclear. 31 In addition, caspase-8 has also been found to be recruited to the focal adhesion complex in NB7 cells in which it enhances cell migration by stimulating talin cleavage by calpains in a caspase-activity/apoptosisindependent manner.…”

Section: Discussionmentioning

confidence: 99%

Mutant PIK3CA licenses TRAIL and CD95L to induce non-apoptotic caspase-8-mediated ROCK activation

et al. 2010

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Constitutively active PI3K catalytic subunit a (PIK3CA) interfered with apoptosis induction downstream of death receptorsignaling complex formation allowing robust caspase-8 activation without triggering the execution steps of apoptosis. In mutant PIK3CA-expressing cells, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD95L stimulated nuclear factor kappaB (NFjB) activation, invasion, and transition to an amoeboid-like morphology. NFjB activation and adoption of amoeboid shape were inhibited by caspase-8 knockdown or FLIP-S expression, but only the cell morphology alterations required caspase-8 activity. Furthermore, we identified caspase-8-mediated, caspase-3-independent cleavage of the protein kinase rho-associated, coiled-coil containing protein kinase 1 as a novel mechanism for acquiring amoeboid shape and enhanced invasiveness in response to TRAIL and CD95L. Taken together, we provide evidence that mutated PIK3CA converts the 'tumor surveillance' activity of cancer cell-expressed death receptors and caspase-8 toward tumor promotion.

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Caspase-8 Interacts with the p85 Subunit of Phosphatidylinositol 3-Kinase to Regulate Cell Adhesion and Motility

Cited by 104 publications

References 18 publications

The pleiotropic effect of TRAIL on tumor-like synovial fibroblasts from rheumatoid arthritis patients is mediated by caspases

The pleiotropic effect of TRAIL on tumor-like synovial fibroblasts from rheumatoid arthritis patients is mediated by caspases

Oncogenic Ras and B-Raf Proteins Positively Regulate Death Receptor 5 Expression through Co-activation of ERK and JNK Signaling

Mutant PIK3CA licenses TRAIL and CD95L to induce non-apoptotic caspase-8-mediated ROCK activation

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