Specific inhibition of basal mitogen-activated protein kinases and phosphatidylinositol 3 kinase activities in leukemia cells: a possible therapeutic role for the kinase inhibitors

Autor: Pierre Champelovier, Virginie Pautre, François Berger, Daniel Seigneurin, Michèle El Atifi, Béatrice Rostaing
Přispěvatelé: AGeing and IMagery (AGIM), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Laboratoire de Neurosciences Précliniques, Université Joseph Fourier - Grenoble 1 (UJF), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Issartel, Jean-Paul
Rok vydání: 2008
Předmět:
MESH: Neoplasm Proteins
MAPK/ERK pathway
Cancer Research
Pyridines
Apoptosis
Cell Cycle Proteins
MESH: Cell Cycle
Mitogen-activated protein kinase kinase
MESH: Monocytes
Monocytes
MESH: Drug Synergism
MAP2K7
0302 clinical medicine
MESH: Protein Kinase Inhibitors
ASK1
Phosphoinositide-3 Kinase Inhibitors
Anthracenes
0303 health sciences
Leukemia
Gene Expression Regulation
Leukemic
Kinase
MESH: Anthracenes
Cell Cycle
MESH: Drug Screening Assays
Antitumor
Imidazoles
Cell Differentiation
Drug Synergism
U937 Cells
Hematology
Neoplasm Proteins
3. Good health
Cell biology
030220 oncology & carcinogenesis
MESH: Gene Expression Regulation
Leukemic
MESH: Cell Division
Mitogen-Activated Protein Kinases
Cell Division
MESH: Imidazoles
MESH: Cell Differentiation
MESH: Cell Line
Tumor
MAP Kinase Signaling System
Morpholines
MESH: Morpholines
HL-60 Cells
MESH: U937 Cells
Biology
03 medical and health sciences
MESH: Cell Cycle Proteins
MESH: HL-60 Cells
Cell Line
Tumor
MESH: Leukemia
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
Genetics
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
c-Raf
Protein Kinase Inhibitors
Molecular Biology
030304 developmental biology
MAPK14
Flavonoids
G protein-coupled receptor kinase
MESH: Humans
MESH: MAP Kinase Signaling System
MESH: Apoptosis
MESH: Pyridines
MESH: 1-Phosphatidylinositol 3-Kinase
Cell Biology
MESH: Mitogen-Activated Protein Kinases
Molecular biology
MESH: Chromones
Chromones
Drug Screening Assays
Antitumor
MESH: Flavonoids
Zdroj: Experimental Hematology
Experimental Hematology, Elsevier, 2008, 36 (1), pp.28-36. ⟨10.1016/j.exphem.2007.08.027⟩
Experimental Hematology, 2008, 36 (1), pp.28-36. ⟨10.1016/j.exphem.2007.08.027⟩
ISSN: 0301-472X
DOI: 10.1016/j.exphem.2007.08.027
Popis: International audience; OBJECTIVE: The roles of phosphatidylinositol 3 (PI3K) and mitogen-activated protein kinases (MAPK) have been widely studied in terms of the differentiation process induced by several drugs (phorbol ester, vitamin D-3, retinoic acid, etc.), but their exact functions in leukemic cells' phenotype and their potential therapeutic role remain incompletely clarified. MATERIALS AND METHODS: In order to investigate this query, leukemia cells were cultured in presence of kinase inhibitors (KIs). Proliferation, apoptosis, and differentiation were analyzed at the cellular and molecular levels, using flow cytometry and reverse transcriptase quantitative polymerase chain reaction. RESULTS: SB203580, a P38 MAPK inhibitor, had no effect on cell proliferation, whereas LY294002, a PI3K inhibitor, and PD098059, a selective inhibitor of mitogen-activated extracellular regulated kinase (MEK) phosphorylation, arrested cells in G(0)/G(1). However, LY294002 and PD098059 acted using different mechanisms: LY294002 decreased the expression of phosphorylated S6RP, whereas PD098059 increased P21/waf1 antigen expression. SP600125, an inhibitor of N-terminal c-jun kinases, arrested cells in G(2) and induced an endoreplicative process. SP600125 increased p21 at both the mRNA and protein levels. G(2) blockage is dependent on the PI3K pathway and the endoreplicative process is dependent on the PI3K and extracellular regulated kinase (ERK) pathways and mRNA synthesis. On the other hand, PD098059 potentiated the apoptotic process induced by either SP600125 or LY294002. Modulation of the expression of CD11, CD15, CD18, and CD54 was cell-dependent. CONCLUSION: Our results suggest that KIs modulate proliferation of leukemia cells and that the MEK/ERK inhibitor, PD098059, in combination with either SP600125 or LY294002, could have clinical value.
Databáze: OpenAIRE
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