Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-x(L), c-Jun, and p21(CIP1), but independent of p53 Journal Article
| Authors: | Vrana, J. A.; Decker, R. H.; Johnson, C. R.; Wang, Z.; Jarvis, W. D.; Richon, V. M.; Ehinger, M.; Fisher, P. B.; Grant, S. |
| Article Title: | Induction of apoptosis in U937 human leukemia cells by suberoylanilide hydroxamic acid (SAHA) proceeds through pathways that are regulated by Bcl-2/Bcl-x(L), c-Jun, and p21(CIP1), but independent of p53 |
| 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-x(L), inhibited SAHA-induced apoptosis, but only modestly potentiated differentiation. While SAHA induced the cyclin-dependent kinase inhibitor p21(CIP1), 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-x(L), p21(CIP1), and the c-Jun/AP-1 signaling cascade. |
| Keywords: | mitogen activated protein kinase; controlled study; leukemia; unclassified drug; oncoprotein; human cell; mutant protein; cell cycle s phase; protein bcl 2; apoptosis; stress activated protein kinase; enzyme degradation; down-regulation; caspase 3; enzyme activation; bcl-x protein; protein p53; myc protein; vorinostat; hydroxamic acids; tumor suppressor protein p53; drug cytotoxicity; cyclin-dependent kinase inhibitor p21; cyclins; mitochondrial membrane; proto-oncogene proteins c-myc; retinoblastoma protein; protein p21; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; proto-oncogene proteins c-myb; proto-oncogene proteins c-bcl-2; cell cycle g1 phase; cell cycle g0 phase; p53; leukemia cell line; differentiation; cell strain u937; u937 cells; hydroxamic acid derivative; saha; 2 (2 amino 3 methoxyphenyl)chromone; protein c jun; protein bcl x; membrane potential; proto-oncogene proteins c-jun; humans; human; priority journal; article; hmba |
| Journal Title: | Oncogene |
| Volume: | 18 |
| Issue: | 50 |
| ISSN: | 0950-9232 |
| Publisher: | Nature Publishing Group |
| Date Published: | 1999-11-25 |
| Start Page: | 7016 |
| End Page: | 7025 |
| Language: | English |
| PUBMED: | 10597302 |
| PROVIDER: | scopus |
| DOI: | 10.1038/sj.onc.1203176 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 16 August 2016 -- Source: Scopus |
