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-81WT 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.
Highlights
BNML model of leukemia, considered reliable to judge the clinical efficacy of anti-leukemic drugs.[5]
The cAMP-induced death is blocked by overexpression of ICER,[9] which competitively inhibits the access of the cAMP-responsive gene promoter elements binding protein (CREB) transcription factor family members to cAMP-responsive elements (CRE).[10]
We found that activation of PKA isozyme I (PKA-I) was necessary and sufficient for cAMP-induced IPC cell death
Summary
BNML model of leukemia, considered reliable to judge the clinical efficacy of anti-leukemic drugs.[5]. Neither Bim induction, CREB activity or RCVinhibitable CDK activity affected anthracycline-induced IPC cell death, which depended on glycogen synthase kinase 3b (GSK3b) activity and was promoted by disruption of the Keywords: CDK7; CDK9; TATA-less; cochaperone p23; roscovitine; CRE Abbreviations: 2-Cl-8-HA-cAMP, 2-chloro-8-hexylamino-adenosine-30,50-cyclic monophosphate; 8-CPT-20-O-Me-cAMP, 8-(4-chlorophenylthio)-20-O-methyladenosine-30,50-cyclic monophosphate; 8-CPT-cAMP, 8-(4-chlorophenylthio)adenosine-30,50-cyclic monophosphate; AML, acute myelogenic leukemia; ATF1, activating transcription factor 1; Bcl-2, B-cell lymhoma 2 oncogene protein; Bim, Bcl-2 interacting mediator of cell death (BCL2L11); CDK, cyclin dependent protein kinase; CHX, cycloheximide; CRE, cAMP responsive element; CREB, CRE binding protein; CREM, CRE modulator; Epac, exchange factor activated by cAMP (Rap GEF 3,4); GA, geldanamycin; GFP, green fluorescent protein; GSK3b , glycogen synthase kinase 3b; ICER, inducible CRE early repressor; IPC-81, Rat AML cell clone (Institut de Pathologie Cellulaire 81); N6-Bnz-8-Pip-cAMP, N6-benzoyl-8-piperdinoadenosine-30,50-cyclic monophosphate; N6ÀMB-cAMP, N6-monobutyryladenosine-30,50-cyclic monophosphate; PKA-I/II, cAMP-dependent protein kinase (Protein kinase A) type I/II; RCV, roscovitine. We conclude that IPC cells have a potent cAMP-induced cell death pathway unexploited by first-line chemotherapeutics
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