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Protein kinase C-dependent activation of the tumor necrosis factor receptor-mediated extrinsic cell death pathway underlies enhanced apoptosis in human myeloid leukemia cells exposed to bryostatin 1 and flavopiridol.
Mol Cancer Ther. 2003 Jan; 2(1):83-93.MC

Abstract

Interactions between the protein kinase C activator bryostatin 1 and the cyclin-dependent kinase (CDK) inhibitor flavopiridol (FP) have been examined in human myeloid leukemia cells (U937 and HL-60). Previous studies have demonstrated synergistic induction of apoptosis in leukemic cells exposed to the potent differentiation-inducer phorbol 12-myristate 13-acetate (PMA) in conjunction with FP [L. Cartee et al., Cancer Res., 61: 2583-2591, 2001]. Although bryostatin 1 (10 nM) is a very weak inducer of differentiation compared with PMA in these cells, coadministration of a minimally toxic concentration of FP (100 nM) did not promote bryostatin 1-related maturation but instead caused a marked increase in mitochondrial damage (e.g., cytochrome c release; loss of Deltapsi(m)), caspase activation, poly(ADP-ribose) polymerase cleavage, and apoptosis. Bryostatin 1/FP-induced apoptosis was significantly diminished in cells ectopically expressing dominant-negative Fas-associated death domain or by coadministration of tumor necrosis factor (TNF)-alpha soluble receptors, implicating the extrinsic pathway in bryostatin 1/FP actions. Enhanced apoptosis in bryostatin 1/FP-treated cells was accompanied by down-regulation of Mcl-1 and a sustained increase in TNF-alpha release. The selective protein kinase C inhibitor GFX blocked TNF-alpha and cytochrome c release in bryostatin 1/FP-treated cells and attenuated apoptosis. Finally, coadministration of bryostatin 1 (or PMA) with FP induced a marked increase in apoptosis in U937 cells ectopically expressing an NH(2)-terminal phosphorylation loop-deleted Bcl-2 protein, which are otherwise highly resistant to FP-mediated lethality. Taken together, these findings suggest that synergistic induction of apoptosis by bryostatin 1 and FP does not stem from disruption of the leukemic cell maturation process but instead results from enhanced release of TNF-alpha and activation of the extrinsic apoptotic cascade, culminating in cell death.

Authors+Show Affiliations

Department of Medicine, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia 23298, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12533676

Citation

Cartee, Leanne, et al. "Protein Kinase C-dependent Activation of the Tumor Necrosis Factor Receptor-mediated Extrinsic Cell Death Pathway Underlies Enhanced Apoptosis in Human Myeloid Leukemia Cells Exposed to Bryostatin 1 and Flavopiridol." Molecular Cancer Therapeutics, vol. 2, no. 1, 2003, pp. 83-93.
Cartee L, Maggio SC, Smith R, et al. Protein kinase C-dependent activation of the tumor necrosis factor receptor-mediated extrinsic cell death pathway underlies enhanced apoptosis in human myeloid leukemia cells exposed to bryostatin 1 and flavopiridol. Mol Cancer Ther. 2003;2(1):83-93.
Cartee, L., Maggio, S. C., Smith, R., Sankala, H. M., Dent, P., & Grant, S. (2003). Protein kinase C-dependent activation of the tumor necrosis factor receptor-mediated extrinsic cell death pathway underlies enhanced apoptosis in human myeloid leukemia cells exposed to bryostatin 1 and flavopiridol. Molecular Cancer Therapeutics, 2(1), 83-93.
Cartee L, et al. Protein Kinase C-dependent Activation of the Tumor Necrosis Factor Receptor-mediated Extrinsic Cell Death Pathway Underlies Enhanced Apoptosis in Human Myeloid Leukemia Cells Exposed to Bryostatin 1 and Flavopiridol. Mol Cancer Ther. 2003;2(1):83-93. PubMed PMID: 12533676.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein kinase C-dependent activation of the tumor necrosis factor receptor-mediated extrinsic cell death pathway underlies enhanced apoptosis in human myeloid leukemia cells exposed to bryostatin 1 and flavopiridol. AU - Cartee,Leanne, AU - Maggio,Sonia C, AU - Smith,Rebecca, AU - Sankala,Heidi M, AU - Dent,Paul, AU - Grant,Steven, PY - 2003/1/21/pubmed PY - 2003/10/4/medline PY - 2003/1/21/entrez SP - 83 EP - 93 JF - Molecular cancer therapeutics JO - Mol Cancer Ther VL - 2 IS - 1 N2 - Interactions between the protein kinase C activator bryostatin 1 and the cyclin-dependent kinase (CDK) inhibitor flavopiridol (FP) have been examined in human myeloid leukemia cells (U937 and HL-60). Previous studies have demonstrated synergistic induction of apoptosis in leukemic cells exposed to the potent differentiation-inducer phorbol 12-myristate 13-acetate (PMA) in conjunction with FP [L. Cartee et al., Cancer Res., 61: 2583-2591, 2001]. Although bryostatin 1 (10 nM) is a very weak inducer of differentiation compared with PMA in these cells, coadministration of a minimally toxic concentration of FP (100 nM) did not promote bryostatin 1-related maturation but instead caused a marked increase in mitochondrial damage (e.g., cytochrome c release; loss of Deltapsi(m)), caspase activation, poly(ADP-ribose) polymerase cleavage, and apoptosis. Bryostatin 1/FP-induced apoptosis was significantly diminished in cells ectopically expressing dominant-negative Fas-associated death domain or by coadministration of tumor necrosis factor (TNF)-alpha soluble receptors, implicating the extrinsic pathway in bryostatin 1/FP actions. Enhanced apoptosis in bryostatin 1/FP-treated cells was accompanied by down-regulation of Mcl-1 and a sustained increase in TNF-alpha release. The selective protein kinase C inhibitor GFX blocked TNF-alpha and cytochrome c release in bryostatin 1/FP-treated cells and attenuated apoptosis. Finally, coadministration of bryostatin 1 (or PMA) with FP induced a marked increase in apoptosis in U937 cells ectopically expressing an NH(2)-terminal phosphorylation loop-deleted Bcl-2 protein, which are otherwise highly resistant to FP-mediated lethality. Taken together, these findings suggest that synergistic induction of apoptosis by bryostatin 1 and FP does not stem from disruption of the leukemic cell maturation process but instead results from enhanced release of TNF-alpha and activation of the extrinsic apoptotic cascade, culminating in cell death. SN - 1535-7163 UR - https://www.unboundmedicine.com/medline/citation/12533676/Protein_kinase_C_dependent_activation_of_the_tumor_necrosis_factor_receptor_mediated_extrinsic_cell_death_pathway_underlies_enhanced_apoptosis_in_human_myeloid_leukemia_cells_exposed_to_bryostatin_1_and_flavopiridol_ L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12533676 DB - PRIME DP - Unbound Medicine ER -