In the erythroleukemic cell line HEL Prostate-apoptosis-response-gene-4 (par-4) fails to down-regulate Bcl-2 and to promote apoptosis

Leuk Lymphoma. 2004 Jul;45(7):1445-51. doi: 10.1080/10428190410001663617.

Abstract

In a variety of malignant cells Prostate-apoptosis-response-gene-4 (Par-4) exhibits a pro-apoptotic influence sensitizing these cells to apoptosis-inducing agents by downregulating expression of Bcl-2. Considering the crucial role of Bcl-2 in the development of chemoresistance of acute myeloid leukemia (AML) cells, we here assessed the potential of Par-4 to down-regulate Bcl-2 and to induce apoptosis in the erythroleukemic cell line HEL. Testing a potential pro-apoptotic role of Par-4 upon incubation with various conventional chemotherapeutic drugs, novel agents such as the signal transduction inhibitor STI 571 and the histone deacetylase (HDAC)- inhibitor trichostatin A (TSA), as well as with the experimental substances Fas and TRAIL, we provide evidence that in the erythroleukemic cell line HEL expression of Par-4 is not sufficient to sensitize to any of these pro-apoptotic stimuli. We further demonstrate that--in contrast to previous reports in non-AML cells--Par-4 expression in HEL cells leads to an upregulation of Bcl-2. Moreover, Par-4-positive HEL cells exhibit a decreased level of the proapoptotic protein Bax as compared to Par-4- negative cells. In addition, Par-4 increases the expression of Daxx--whose downregulation is associated with augmented chemosensitivity--as well as expression of the procaspases-8, -9 and -10, whereas the levels of the procaspases-3 and -7 remain unaltered. In conclusion we here demonstrate that in the erythroleukemic cell line HEL--in contrast to other cell types Par-4 fails to promote apoptosis and outline the underlying molecular mechanisms.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Benzamides
  • Carrier Proteins / biosynthesis
  • Carrier Proteins / genetics
  • Carrier Proteins / physiology*
  • Caspase 10
  • Caspase 8
  • Caspase 9
  • Caspases / biosynthesis
  • Caspases / genetics
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism*
  • Cell Line, Tumor / pathology
  • Co-Repressor Proteins
  • Enzyme Precursors / biosynthesis
  • Enzyme Precursors / genetics
  • Gene Expression Regulation, Leukemic* / drug effects
  • Genes, bcl-2*
  • Histone Deacetylase Inhibitors
  • Humans
  • Hydroxamic Acids / pharmacology
  • Imatinib Mesylate
  • Intracellular Signaling Peptides and Proteins*
  • Leukemia, Erythroblastic, Acute / genetics
  • Leukemia, Erythroblastic, Acute / pathology*
  • Membrane Glycoproteins / agonists
  • Molecular Chaperones
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins / biosynthesis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Pyrimidines / pharmacology
  • TNF-Related Apoptosis-Inducing Ligand
  • Transfection
  • Tumor Necrosis Factor-alpha / agonists
  • bcl-2-Associated X Protein
  • fas Receptor / drug effects

Substances

  • Adaptor Proteins, Signal Transducing
  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BAX protein, human
  • Benzamides
  • Carrier Proteins
  • Co-Repressor Proteins
  • DAXX protein, human
  • Enzyme Precursors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Intracellular Signaling Peptides and Proteins
  • Membrane Glycoproteins
  • Molecular Chaperones
  • Neoplasm Proteins
  • Nuclear Proteins
  • Piperazines
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrimidines
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • bcl-2-Associated X Protein
  • fas Receptor
  • prostate apoptosis response-4 protein
  • trichostatin A
  • Imatinib Mesylate
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 10
  • Caspase 8
  • Caspase 9
  • Caspases
  • CASP10 protein, human