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Staurosporine resistance in inflammatory neutrophils is associated with the inhibition of caspase- and proteasome-mediated Mcl-1 degradation
- Source :
- Journal of leukocyte biology. 99(1)
- Publication Year :
- 2015
-
Abstract
- Apoptosis resistance in activated neutrophils is known to be associated with collateral damage of surrounding tissue, as well as immune and organ dysfunction. Thus, the safe removal of neutrophils by apoptosis induction represents a prerequisite for the resolution of inflammation. Here, we report that intrinsic apoptosis resistance in human neutrophils, isolated from severely injured patients, is based on enhanced stabilization of antiapoptotic myeloid cell leukemia 1 and subsequent impairment of downstream apoptotic pathways. Whereas extrinsic apoptosis induction by the activation of Fas death receptor on inflammatory neutrophils was accompanied by caspase- and proteasome-mediated myeloid cell leukemia 1 degradation, intrinsic apoptosis induction by staurosporine led to a significant stabilization of myeloid cell leukemia 1 protein, which impeded on truncated forms of B cell lymphoma 2-associated X protein and B cell lymphoma 2 homology domain 3-interacting domain death translocation and subsequent cytochrome c release from the mitochondria. We show further that profound inhibition of myeloid cell leukemia 1 degradation is based on the inhibition of caspases and sustained activation of kinases involved in cell survival, such as Akt. Accordingly, impeded myeloid cell leukemia 1 phosphorylation on Ser159 by glycogen synthase kinase 3 and protein ubiquitination has been demonstrated. Inhibition of myeloid cell leukemia 1 activity markedly increased sensitivity to staurosporine-induced cell death. Altogether, these results provide new insights into the mechanisms underlying myeloid cell leukemia 1-mediated apoptosis resistance to staurosporine under inflammatory situations and should be considered for the development of novel therapeutic strategies.
- Subjects :
- 0301 basic medicine
Programmed cell death
Proteasome Endopeptidase Complex
Myeloid
Neutrophils
Immunology
Drug Resistance
Apoptosis
03 medical and health sciences
hemic and lymphatic diseases
medicine
Immunology and Allergy
Staurosporine
Humans
Prospective Studies
Enzyme Inhibitors
Protein kinase B
Caspase
Inflammation
biology
Inflammation, Extracellular Mediators, & Effector Molecules
Intrinsic apoptosis
Cell Biology
medicine.disease
Cell biology
Mitochondria
Enzyme Activation
Leukemia
030104 developmental biology
medicine.anatomical_structure
Case-Control Studies
Caspases
Proteolysis
biology.protein
Myeloid Cell Leukemia Sequence 1 Protein
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 19383673
- Volume :
- 99
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of leukocyte biology
- Accession number :
- edsair.doi.dedup.....80896b758c91da4ff6d3b13fb480156c