title: Cyclic AMP induces IPC leukemia cell apoptosis via CRE-and CDK-dependent Bim transcription.
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.
authors.affiliation: Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Huseby
authors.forename: G
authors.initials: G
authors.lastname: Gausdal
authors.forename: T J
authors.initials: TJ
authors.lastname: Keen
authors.forename: E
authors.initials: E
authors.lastname: Kjærland
authors.forename: C
authors.initials: C
authors.lastname: Krakstad
authors.forename: L
authors.initials: L
authors.lastname: Myhren
authors.forename: K
authors.initials: K
authors.lastname: Brønstad
authors.forename: C
authors.initials: C
authors.lastname: Kunick
authors.forename: F
authors.initials: F
authors.lastname: Schwede
authors.forename: H-G
authors.initials: HG
authors.lastname: Genieser
authors.forename: R
authors.initials: R
authors.lastname: Kleppe
authors.forename: S O
authors.initials: SO
authors.lastname: Døskeland
mesh_terms: D051698:Activating Transcription Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D051786:Cyclic AMP Response Element Modulator / Q000378:metabolism; D054743:Cyclic AMP-Dependent Protein Kinase Type I / Q000378:metabolism; D054746:Cyclic AMP-Dependent Protein Kinase Type II / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D003630:Daunorubicin / Q000494:pharmacology; D004357:Drug Synergism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D007938:Leukemia / Q000503:physiopathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D014158:Transcription, Genetic
chemical_list: D051698:Activating Transcription Factor 2; D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606778:Bcl2l11 protein, rat; D016227:Benzoquinones; C497412:Crem protein, rat; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051786:Cyclic AMP Response Element Modulator; D000242:Cyclic AMP; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D054743:Cyclic AMP-Dependent Protein Kinase Type I; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; C001277:geldanamycin; D003630:Daunorubicin