Phosphatidylserine exposure in Fas type I cells is mitochondria‐dependent

Uthaisang, Wanlaya; Nutt, Leta K.; Orrenius, Sten; Fadeel, Bengt

doi:10.1016/s0014-5793(03)00508-8

Cited by 24 publications

(21 citation statements)

References 22 publications

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“…Furthermore, PS externalization and clearance of apoptotic cells are mitochondria-dependent events, which are regulated by Bcl-2, and dissociated from other features of the apoptotic program. 124 This may explain the finding in the previous report that apoptotic cells induced by etoposide and staurosporine treatment were not efficiently ingested: unengulfed apoptotic cells were consistently present at all doses and time points, even when treated cells were mixed with healthy and untreated cells. 125 For any immunomodulatory anticancer treatment to be effective, it is necessary to reverse an immunosuppressive situation.…”

Section: Discussionmentioning

confidence: 60%

Cancer cell immune escape and tumor progression by exploitation of anti-inflammatory and pro-inflammatory responses

Kim¹,

Emi²,

Tanabe³

2005

Cancer Biology & Therapy

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Apoptotic cells can be eliminated by phagocytosis, which is mediated by antigen-presenting cells (APCs), such as macrophages and dendritic cells (DCs), through phosphatidylserine (PS) on apoptotic cells and phosphatidylserine receptor (PSR) on APCs. The phagocytosis of apoptotic cells by macrophages is strictly regulated by not only the inflammatory reaction, but also by an increase in anti-inflammatory factors such as IL-10, TGF-β, and prostaglandin E 2 (PGE 2 ), leading to an anti-inflammatory situation, whereby apoptosis contributes to a noninflammatory response. However, because PS and PSR are expressed in cancer cells, shed soluble phosphatidylserine (sPS) can interact with the PS receptor on macrophages, which promotes an anti-inflammatory response to macrophages that may lead to immune escape. The sPS derived from cancer cells also reacts with the PSR on the cancer cells to produce IL-10, TGF-β, and PGE 2 , which can cause suppression of anti-tumor immunity through the anti-inflammatory response to macrophages, which produces tumor-associated macrophages. Furthermore, sPS and TGF-β inhibit the maturation of immature DCs, resulting in a functional inhibition of DCs. The potential roles of PS and PSR in cancer cells and macrophages in immune escape mediated by sPS and anti-inflammatory factors are discussed, which may explain their dual regulation of anti-and pro-inflammatory responses during tumor progression.

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Section: Discussionmentioning

confidence: 60%

Cancer cell immune escape and tumor progression by exploitation of anti-inflammatory and pro-inflammatory responses

Kim¹,

Emi²,

Tanabe³

2005

Cancer Biology & Therapy

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“…Phosphatidylserine (PS) exposure was determined by flow cytometric detection of the PS-binding protein annexin V using the annexin V-FITC apoptosis detection kit (Oncogene Research Products, Cambridge, MA), as described previously (Uthaisang et al, 2003). Cells were costained with propidium iodide (PI) prior to analysis on a FACScan (Becton Dickinson, San Jose, CA) equipped with a 488-nm argon laser.…”

Section: Methodsmentioning

confidence: 99%

Requirement of Apoptotic Protease-Activating Factor-1 for Bortezomib-Induced Apoptosis but Not for Fas-Mediated Apoptosis in Human Leukemic Cells

Ottosson-Wadlund¹,

Ceder²,

Preta³

et al. 2012

Mol Pharmacol

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Bortezomib is a highly selective inhibitor of the 26S proteasome and has been approved for clinical use in the treatment of relapsing and refractory multiple myeloma and mantle cell lymphoma. Clinical trials are also underway to assess the role of bortezomib in several other human malignancies, including leukemia. However, the mechanism(s) by which bortezomib acts remain to be fully understood. Here, we studied the molecular requirements of bortezomib-induced apoptosis using the human T-cell leukemic Jurkat cells stably transfected with or without shRNA against apoptotic protease-activating factor-1 (Apaf-1). The Apaf-1-deficient Jurkat T cells were resistant to bortezomibinduced apoptosis, as assessed by caspase-3 activity, poly(ADPribose) polymerase cleavage, phosphatidylserine externalization, and hypodiploid DNA content. In contrast, Apaf-1-deficient cells were sensitive to Fas-induced apoptosis. Bortezomib induced an upregulation of the pro-apoptotic protein Noxa, loss of mitochondrial transmembrane potential, and release of cytochrome c in cells expressing or not expressing Apaf-1. Transient silencing of Apaf-1 expression in RPMI 8402 T-cell leukemic cells also diminished bortezomib-induced apoptosis. Fas-associated death domain (FADD)-deficient Jurkat cells were resistant to Fas-mediated apoptosis yet remained sensitive to bortezomib. Our results show that bortezomib induces apoptosis by regulating pathways that are mechanistically different from those activated upon death receptor ligation. Furthermore, in silico analyses of public transcriptomics databases indicated elevated Apaf-1 expression in several hematologic malignancies, including acute lymphoblastic and myeloid leukemia. We also noted variable Apaf-1 expression in a panel of samples from patients with acute lymphoblastic leukemia. Our results suggest that the expression of Apaf-1 may be predictive of the response to proteasome inhibition.

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“…Nuclear Fragmentation-Nuclear condensation/fragmentation of Hoechst 33342 (1 g/ml)-labeled cells was evaluated as described previously (22). Cells were scored using a fluorescence microscope (Nikon ECLIPSE TE 200, Tokyo, Japan) equipped with a digital Hamamatsu CCD camera (C4742-95-12NBR).…”

Section: Methodsmentioning

confidence: 99%

“…Reportedly, APLT is not a substrate for apoptosis-activated caspases suggesting that alternative mechanisms may be involved (20). In line with this, PS externalization can be divorced from the common caspase-initiated pathway of apoptosis (21,22). Connor and Schroit (23) demonstrated that reversible PS externalization can be induced by -SH reagents in non-apoptotic cells.…”

mentioning

confidence: 96%

Nitrosative Stress Inhibits the Aminophospholipid Translocase Resulting in Phosphatidylserine Externalization and Macrophage Engulfment

Tyurina

Basova

Konduru

et al. 2007

Journal of Biological Chemistry

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Macrophage recognition of apoptotic cells depends on externalization of phosphatidylserine (PS), which is normally maintained within the cytosolic leaflet of the plasma membrane by aminophospholipid translocase (APLT). APLT is sensitive to redox modifications of its -SH groups. Because activated macrophages produce reactive oxygen and nitrogen species, we hypothesized that macrophages can directly participate in apoptotic cell clearance by S-nitrosylation/oxidation and inhibition of APLT causing PS externalization. Here we report that exposure of target HL-60 cells to nitrosative stress inhibited APLT, induced PS externalization, and enhanced recognition and elimination of "nitrosatively" modified cells by RAW 264.7 macrophages. Using S-nitroso-L-cysteine-ethyl ester (SNCEE) and S-nitrosoglutathione (GSNO) that cause intracellular and extracellular trans-nitrosylation of proteins, respectively, we found that SNCEE (but not GSNO) caused significant S-nitrosylation/ oxidation of thiols in HL-60 cells. SNCEE also strongly inhibited APLT, activated scramblase, and caused PS externalization. However, SNCEE did not induce caspase activation or nuclear condensation/fragmentation suggesting that PS externalization was dissociated from the common apoptotic pathway. Dithiothreitol reversed SNCEE-induced S-nitrosylation, APLT inhibition, and PS externalization. SNCEE but not GSNO stimulated phagocytosis of HL-60 cells. Moreover, phagocytosis of target cells by lipopolysaccharide-stimulated macrophages was significantly suppressed by an NO ⅐ scavenger, DAF-2. Thus, macrophage-induced nitrosylation/oxidation plays an important role in cell clearance, and hence in the resolution of inflammation.

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Phosphatidylserine exposure in Fas type I cells is mitochondria‐dependent

Cited by 24 publications

References 22 publications

Cancer cell immune escape and tumor progression by exploitation of anti-inflammatory and pro-inflammatory responses

Cancer cell immune escape and tumor progression by exploitation of anti-inflammatory and pro-inflammatory responses

Requirement of Apoptotic Protease-Activating Factor-1 for Bortezomib-Induced Apoptosis but Not for Fas-Mediated Apoptosis in Human Leukemic Cells

Nitrosative Stress Inhibits the Aminophospholipid Translocase Resulting in Phosphatidylserine Externalization and Macrophage Engulfment

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