Abstract
The interaction between retinoids and transforming growth factor-beta1 (TGF-beta1) leading to regulation of proliferation, differentiation and apoptosis is not still fully understood. In this study, we demonstrated that a combination treatment with all-trans retinoic acid (ATRA) and TGF-beta1 led to the enhancement of ATRA-induced suppression of cell proliferation, which is accompanied by inhibition of ATRA-induced apoptosis in human leukemia HL-60 cells. This effect was preceded by the arrest of cells in G0/G1 cell cycle phase linked with pRb protein dephosphorylation, continuous accumulation of p21 and transiently increased level of p27, inhibitors of cyclin-dependent kinases. Inhibition of ATRA-induced apoptosis by TGF-beta1 was associated with an increased level of Mcl-1 protein, an anti-apoptotic member of Bcl-2 family, but not with inhibition of mitochondrial membrane depolarization. Levels of other Bcl-2 family proteins (Bcl-2, Bcl-X(L), Bad, Bak, Bax) were unaffected by simultaneous ATRA and TGF-beta1 treatment, when compared to ATRA alone. Upregulation of c-FLIP(L) protein, an inhibitor of apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), correspond with inhibition of ATRA-induced (autocrine TRAIL-mediated) caspase-8 activation and apoptosis. These results suggest that apoptosis inhibition associated with proliferation block could depend on modulation of the TRAIL apoptotic pathway and regulation of the Mcl-1 protein level. In summary, we demonstrate that the balance of processes leading to regulation of proliferation and differentiation of myeloid cells can modulate cell sensitivity to apoptosis-inducing stimuli.
MeSH terms
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Apoptosis / drug effects*
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Apoptosis / physiology
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis Regulatory Proteins / pharmacology
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CD11b Antigen / biosynthesis
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CD11b Antigen / drug effects
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Caspase 3
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Caspase 8
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Caspases / drug effects
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Caspases / metabolism
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Cell Cycle / drug effects
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Cell Differentiation / drug effects
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
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Cyclin-Dependent Kinase Inhibitor p21 / drug effects
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Drug Synergism
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Enzyme Activation / drug effects
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G1 Phase / drug effects
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Granulocytes / drug effects
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Granulocytes / physiology
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HL-60 Cells
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Humans
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Intracellular Signaling Peptides and Proteins / drug effects
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Intracellular Signaling Peptides and Proteins / metabolism
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / pharmacology
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Mitochondrial Membranes / drug effects
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Mitochondrial Membranes / physiology
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / drug effects
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Neoplasm Proteins / metabolism
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Phosphorylation
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Proto-Oncogene Proteins c-bcl-2 / drug effects
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Reactive Oxygen Species / metabolism
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Resting Phase, Cell Cycle / drug effects
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Retinoblastoma Protein / drug effects
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Retinoblastoma Protein / metabolism
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TNF-Related Apoptosis-Inducing Ligand
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Transforming Growth Factor beta / pharmacology*
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Transforming Growth Factor beta1
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Tretinoin / antagonists & inhibitors*
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Tretinoin / pharmacology
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
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bcl-2-Associated X Protein / drug effects
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bcl-2-Associated X Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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BAX protein, human
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CD11b Antigen
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CDKN1A protein, human
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CFLAR protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Proto-Oncogene Proteins c-bcl-2
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Reactive Oxygen Species
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Retinoblastoma Protein
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TGFB1 protein, human
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Transforming Growth Factor beta
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Transforming Growth Factor beta1
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Tumor Necrosis Factor-alpha
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bcl-2-Associated X Protein
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Tretinoin
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CASP3 protein, human
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CASP8 protein, human
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Caspase 3
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Caspase 8
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Caspases