Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53
(1999) In Oncogene 18(50). p.25-7016- Abstract
Determinants of differentiation and apoptosis in myelomonocytic leukemia cells (U937) exposed to the novel hybrid polar compound SAHA (suberoylanilide hydroxamic acid) have been examined. In contrast to hexamethylenbisacetamide (HMBA), SAHA-related maturation was limited and accompanied by marked cytoxicity. SAHA-mediated apoptosis occurred within the G0G1 and S phase populations, and was associated with decreased mitochondrial membrane potential, caspase-3 activation, PARP degradation, hypophosphorylation/cleavage of pRB, and down-regulation of c-Myc, c-Myb, and B-Myb. Enforced expression of Bcl-2 or Bcl-XL inhibited SAHA-induced apoptosis, but only modestly potentiated differentiation. While SAHA induced the cyclin-dependent kinase... (More)
Determinants of differentiation and apoptosis in myelomonocytic leukemia cells (U937) exposed to the novel hybrid polar compound SAHA (suberoylanilide hydroxamic acid) have been examined. In contrast to hexamethylenbisacetamide (HMBA), SAHA-related maturation was limited and accompanied by marked cytoxicity. SAHA-mediated apoptosis occurred within the G0G1 and S phase populations, and was associated with decreased mitochondrial membrane potential, caspase-3 activation, PARP degradation, hypophosphorylation/cleavage of pRB, and down-regulation of c-Myc, c-Myb, and B-Myb. Enforced expression of Bcl-2 or Bcl-XL inhibited SAHA-induced apoptosis, but only modestly potentiated differentiation. While SAHA induced the cyclin-dependent kinase inhibitor p21CIP1, antisense ablation of this CDKI increased, rather than decreased, SAHA-related lethality. In contrast, conditional expression of wild-type p53 failed to modify SAHA actions, but markedly potentiated HMBA-induced apoptosis. Finally, SAHA modestly increased expression/activation of the stress-activated protein kinase (SAPK/JNK); moreover, SAHA-related lethality was partially attenuated by a dominant-negative c-Jun mutant protein (TAM67). SAHA did not stimulate mitogen-activated protein kinase (MAPK), nor was lethality diminished by the specific MEK/MAPK inhibitor PD98059. These findings indicate that SAHA potently induces apoptosis in human leukemia cells via a pathway that is p53-independent but at least partially regulated by Bcl-2/Bcl-XL, p21CIP1, and the c-Jun/AP-1 signaling cascade.
(Less)
- author
- Vrana, J A ; Decker, R H ; Johnson, C R ; Wang, Z ; Jarvis, W D ; Richon, V M ; Ehinger, M LU ; Fisher, P B and Grant, S
- publishing date
- 1999
- type
- Contribution to journal
- publication status
- published
- keywords
- Apoptosis/drug effects, Cyclin-Dependent Kinase Inhibitor p21, Cyclins/metabolism, Down-Regulation, Humans, Hydroxamic Acids/pharmacology, Leukemia/metabolism, Proto-Oncogene Proteins c-bcl-2/metabolism, Proto-Oncogene Proteins c-jun/metabolism, Proto-Oncogene Proteins c-myb/metabolism, Proto-Oncogene Proteins c-myc/metabolism, Tumor Suppressor Protein p53/metabolism, U937 Cells, Vorinostat, bcl-X Protein
- in
- Oncogene
- volume
- 18
- issue
- 50
- pages
- 25 - 7016
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:0033604457
- pmid:10597302
- ISSN
- 0950-9232
- DOI
- 10.1038/sj.onc.1203176
- language
- English
- LU publication?
- no
- id
- ad7b16e2-0d17-4bb1-afdb-dbe5c63f28b0
- date added to LUP
- 2022-01-23 15:30:17
- date last changed
- 2024-04-06 16:15:42
@article{ad7b16e2-0d17-4bb1-afdb-dbe5c63f28b0,
abstract = {{<p>Determinants of differentiation and apoptosis in myelomonocytic leukemia cells (U937) exposed to the novel hybrid polar compound SAHA (suberoylanilide hydroxamic acid) have been examined. In contrast to hexamethylenbisacetamide (HMBA), SAHA-related maturation was limited and accompanied by marked cytoxicity. SAHA-mediated apoptosis occurred within the G0G1 and S phase populations, and was associated with decreased mitochondrial membrane potential, caspase-3 activation, PARP degradation, hypophosphorylation/cleavage of pRB, and down-regulation of c-Myc, c-Myb, and B-Myb. Enforced expression of Bcl-2 or Bcl-XL inhibited SAHA-induced apoptosis, but only modestly potentiated differentiation. While SAHA induced the cyclin-dependent kinase inhibitor p21CIP1, antisense ablation of this CDKI increased, rather than decreased, SAHA-related lethality. In contrast, conditional expression of wild-type p53 failed to modify SAHA actions, but markedly potentiated HMBA-induced apoptosis. Finally, SAHA modestly increased expression/activation of the stress-activated protein kinase (SAPK/JNK); moreover, SAHA-related lethality was partially attenuated by a dominant-negative c-Jun mutant protein (TAM67). SAHA did not stimulate mitogen-activated protein kinase (MAPK), nor was lethality diminished by the specific MEK/MAPK inhibitor PD98059. These findings indicate that SAHA potently induces apoptosis in human leukemia cells via a pathway that is p53-independent but at least partially regulated by Bcl-2/Bcl-XL, p21CIP1, and the c-Jun/AP-1 signaling cascade.</p>}},
author = {{Vrana, J A and Decker, R H and Johnson, C R and Wang, Z and Jarvis, W D and Richon, V M and Ehinger, M and Fisher, P B and Grant, S}},
issn = {{0950-9232}},
keywords = {{Apoptosis/drug effects; Cyclin-Dependent Kinase Inhibitor p21; Cyclins/metabolism; Down-Regulation; Humans; Hydroxamic Acids/pharmacology; Leukemia/metabolism; Proto-Oncogene Proteins c-bcl-2/metabolism; Proto-Oncogene Proteins c-jun/metabolism; Proto-Oncogene Proteins c-myb/metabolism; Proto-Oncogene Proteins c-myc/metabolism; Tumor Suppressor Protein p53/metabolism; U937 Cells; Vorinostat; bcl-X Protein}},
language = {{eng}},
number = {{50}},
pages = {{25--7016}},
publisher = {{Nature Publishing Group}},
series = {{Oncogene}},
title = {{Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-XL, c-Jun, and p21CIP1, but independent of p53}},
url = {{http://dx.doi.org/10.1038/sj.onc.1203176}},
doi = {{10.1038/sj.onc.1203176}},
volume = {{18}},
year = {{1999}},
}