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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

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 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.

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Abbreviations

ERK:

extracellular receptor kinase

HMBA:

hexamethy-lenebisacetamide

JNK:

Jun N-terminal kinase

MAPK:

mitogen-activated protein kinase

PMA:

phorbol myristate acetate

SAHA:

suberoylanilide hydroxamic acid

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Acknowledgements

We would like to thank E Freeman, A Nambiar, G Schaefer and J-H Chen for their technical assistance. This work was supported by awards CA63753, CA72955, CA77141, CA35675 from the NIH, award 6405-97 from the Leukemia Society of America, and the Chernow Endowment Trust. PB Fisher is the Michael and Stella Chernow Urological Research Scientist.

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Vrana, J., Decker, R., Johnson, C. et al. 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. Oncogene 18, 7016–7025 (1999). https://doi.org/10.1038/sj.onc.1203176

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