Arsenic-interferon-alpha-triggered apoptosis in HTLV-I transformed cells is associated with tax down-regulation and reversal of NF-kappa B activation.
Human T-cell lymphotropic virus type I (HTLV-I)-associated adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature activated T cells resistant to conventional chemotherapy. The viral transactivator protein Tax plays a critical role in HTLV-I-induced transformation and apoptosis resistance by inducing I kappa B-alpha degradation, resulting in the activation of the NF-kappa Bpathway. In these HTLV-I-transformed cells, arsenic trioxide (As) and interferon (IFN)-alpha synergize to induce cell cycle arrest and apoptosis. We demonstrate that cell death induction is only partly dependent upon caspase activation and is not associated with modulation of bcl-2, bax, or p53 expression. However, combined As and IFN induce the degradation of Tax, associated with an up-regulation of I kappa B-alpha resulting in a sharp decrease in RelA DNA binding nuclear factor (NF)-kappa B complexes because of the cytoplasmic retention of RelA. Taken the role of Tax in HTLV-I-induced transformation, its down-regulation probably accounts for cell death induction through inactivation of the NF-kappa B pathway. Such specific targeting of the viral oncoprotein by As-IFN treatment, reminiscent of As targeting of promyelocytic leukemia/retinoic acid receptor-alpha in acute promyelocytic leukemia, provides strong rational for combined As-IFN therapy in ATL patients. (Blood. 2000;96:2849-2855)
El-Sabban
M E
ME
Department of Human Morphology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Nasr
R
R
Dbaibo
G
G
Hermine
O
O
Abboushi
N
N
Quignon
F
F
Ameisen
J C
JC
Bex
F
F
de Thé
H
H
Bazarbachi
A
A
D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D020169:Caspases / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral / Q000187:drug effects*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D016356:Gene Products, tax / Q000502:physiology*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins; D016898:Interferon-alpha / Q000494:pharmacology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000473:pathology; D008025:Ligases / Q000378:metabolism; D046911:Macromolecular Substances; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000502:physiology*; D010087:Oxides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D015533:Transcriptional Activation / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D001152:Arsenicals; D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D020672:I-kappa B Proteins; D016898:Interferon-alpha; D046911:Macromolecular Substances; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; D010087:Oxides; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D020169:Caspases; D008025:Ligases; C028812:guanosine 3',5'-polyphosphate synthetases; D000077237:Arsenic Trioxide