Abstract
All-trans retinoic acid (ATRA) resistance has been a critical problem in acute promyelocytic leukemia (APL) relapsed patients. In ATRA resistant APL cell lines NB4-R1 and NB4-R2, the combination of staurosporine and ATRA synergized to trigger differentiation accompanied by significantly enhanced protein level of CCAAT/enhancer binding protein ε (C/EBPε) and C/EBPβ as well as the phosphorylation of mitogen-activated protein (MEK) and extracellular signal-regulated kinase (ERK). Furthermore, attenuation of the MEK activation blocked not only the differentiation but also the increased protein level of C/EBPε and C/EBPβ. Taken together, we concluded that the combination of ATRA and staurosporine could overcome differentiation block via MEK/ERK signaling pathway in ATRA-resistant APL cell lines.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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CCAAT-Enhancer-Binding Proteins / metabolism
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Cell Differentiation / drug effects*
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Cell Differentiation / genetics
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm* / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Granulocytes / drug effects
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Granulocytes / pathology
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Humans
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Leukemia, Promyelocytic, Acute / genetics
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Leukemia, Promyelocytic, Acute / metabolism
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Leukemia, Promyelocytic, Acute / pathology*
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Mitogen-Activated Protein Kinases / metabolism
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism
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Phosphorylation
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Staurosporine / analogs & derivatives*
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Tretinoin / pharmacology*
Substances
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CCAAT-Enhancer-Binding Proteins
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Oncogene Proteins, Fusion
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promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
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Tretinoin
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinases
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Staurosporine