In bcr-abl-positive myeloid cells resistant to conventional chemotherapeutic agents, expression of Par-4 increases sensitivity to imatinib (STI571) and histone deacetylase-inhibitors.
In a variety of malignant cells the prostate-apoptosis-response-gene-4 (Par-4) induces increased sensitivity towards chemotherapeutic agents by down-regulating anti-apoptotic B-cell lymphoma-gene 2 (Bcl-2). Hypothesizing that Par-4 also influences apoptosis in myeloid cell lines, we tested this hypothesis by stably transfecting bcr-abl transformed-K562 cells with a Par-4-expressing vector. Here we demonstrate that over-expression of Par-4 in K562 cells up-regulates expression levels of Bcl-2 and death-associated protein (Daxx). Upon treatment with different chemotherapeutic agents, Fas- or TRAIL agonistic antibodies, Par-4-positive cells did not exhibit an increased rate of apoptosis as compared to Par-4-negative control cells. However, incubation with histone deacetylase (HDAC)-inhibitors Trichostatin A (TSA) and LAQ824 or the tyrosinkinase inhibitor Imatinib (STI571) increased the rate of apoptosis in Par-4-positive K562 cells. Assessing the underlying molecular mechanisms for the Par-4-induced response to HDAC-inhibitors and STI571 we provide evidence, that these effects are associated with a down-regulation of Daxx, enforced activation of caspases and enhanced cleavage of cellular inhibitor of apoptosis (cIAP)-1 and -2.
Brieger
Angela
A
Department of Internal Medicine III, Hematology and Oncology, Johann Wolfgang Goethe-University Hospital, 60590 Frankfurt am Main, Germany.
Boehrer
Simone
S
Schaaf
Simone
S
Nowak
Daniel
D
Ruthardt
Martin
M
Kim
Soo-Zin
SZ
Atadja
Peter
P
Hoelzer
Dieter
D
Mitrou
Paris S
PS
Weidmann
Eckhart
E
Chow
Kai Uwe
KU
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001549:Benzamides; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D056970:Co-Repressor Proteins; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D000068877:Imatinib Mesylate; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D018832:Molecular Chaperones; D022423:Myeloid Cells / Q000187:drug effects; D009687:Nuclear Proteins / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001549:Benzamides; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; C477361:LAQ824; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D010879:Piperazines; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C101296:prostate apoptosis response-4 protein; C012589:trichostatin A; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D020169:Caspases