Abstract
The IPC-81 cell line is derived from the transplantable BNML model of acute myelogenic leukemia (AML), known to be a reliable predictor of the clinical efficiency of antileukemic agents, like the first-line AML anthracycline drug daunorubicin (DNR). We show here that cAMP acted synergistically with DNR to induce IPC cell death. The DNR-induced death differed from that induced by cAMP by (1) not involving Bim induction, (2) being abrogated by GSK3β inhibitors, (3) by being promoted by the HSP90/p23 antagonist geldanamycin and truncated p23 and (4) by being insensitive to the CRE binding protein (CREB) antagonist ICER and to cyclin-dependent protein kinase (CDK) inhibitors. In contrast, the apoptosis induced by cAMP correlated tightly with Bim protein expression. It was abrogated by Bim (BCL2L11) downregulation, whether achieved by the CREB antagonist ICER, by CDK inhibitors, by Bim-directed RNAi, or by protein synthesis inhibitor. The forced expression of BimL killed IPC-81(WT) cells rapidly, Bcl2-overexpressing cells being partially resistant. The pivotal role of CREB and CDK activity for Bim transcription is unprecedented. It is also noteworthy that newly developed cAMP analogs specifically activating PKA isozyme I (PKA-I) were able to induce IPC cell apoptosis. Our findings support the notion that AML cells may possess targetable death pathways not exploited by common anti-cancer agents.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Activating Transcription Factor 2 / antagonists & inhibitors
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Activating Transcription Factor 2 / metabolism*
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Apoptosis Regulatory Proteins / antagonists & inhibitors
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Apoptosis* / drug effects
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Bcl-2-Like Protein 11
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Benzoquinones / pharmacology
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Cell Line, Tumor
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Cyclic AMP / analogs & derivatives
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Cyclic AMP / metabolism*
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Cyclic AMP / pharmacology
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Cyclic AMP Response Element Modulator / metabolism
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Cyclic AMP-Dependent Protein Kinase Type I / metabolism
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Cyclic AMP-Dependent Protein Kinase Type II / metabolism
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclin-Dependent Kinases / metabolism*
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Cyclin-Dependent Kinases / physiology
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Daunorubicin / pharmacology
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Drug Synergism
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Glycogen Synthase Kinase 3 / antagonists & inhibitors
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Lactams, Macrocyclic / pharmacology
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Leukemia / physiopathology
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA Interference
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Rats
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Transcription, Genetic*
Substances
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Activating Transcription Factor 2
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Antibiotics, Antineoplastic
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Bcl2l11 protein, rat
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Benzoquinones
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Crem protein, rat
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Lactams, Macrocyclic
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Membrane Proteins
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Proto-Oncogene Proteins
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Cyclic AMP Response Element Modulator
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Cyclic AMP
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, rat
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Cyclic AMP-Dependent Protein Kinase Type I
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Cyclic AMP-Dependent Protein Kinase Type II
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Cyclin-Dependent Kinases
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Glycogen Synthase Kinase 3
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geldanamycin
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Daunorubicin