Down-regulating constitutive activation of the NF-kappaB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis.
Constitutive activation of the nuclear factor-kappaB (NF-kappaB) pathway has been shown to be involved in the resistance of tumor cells to apoptosis in several human malignancies of the hematopoietic lineage. By using electrophoretic mobility shift assay (EMSA) and confocal microscopic analysis, we demonstrate that NF-kappaB is constitutively activated in cutaneous T-cell lymphoma (CTCL) cell lines HuT-78, MyLa, and SeAx and in peripheral blood lymphocytes (PBLs) from patients with Sézary syndrome (SS) presenting a high ratio of tumor cells, with evidence of p50 and RelA/p65 in DNA-linked complexes. Transfection of SeAx line with a kappaB/luciferase reporter plasmid showed that translocated NF-kappaB complexes were functional. Selective inhibition of NF-kappaB, by transfecting CTCL cell lines with a super-repressor form of IkappaB alpha, led to apoptosis. We evidenced down-regulation of NF-kappaB activation and induction of CTCL cell apoptosis in the presence of proteasome 26S inhibitors ALLN, MG132, and bortezomib. Bortezomib at nanomolar concentrations inhibited constitutive activation of NF-kappaB and induced apoptosis of CTCL cells, with evidence of an upregulation of Bax expression. These results demonstrate the key role played by NF-kappaB in the resistance of CTCL to apoptosis and suggest that bortezomib might be useful for the treatment of patients with advanced stages of CTCL refractory to standard antineoplastic chemotherapy.
Sors
Aurore
A
INSERM U697, Institut de Recherche sur la Peau, Pavillon Bazin, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75475 Paris cedex 10, France.
Jean-Louis
Francette
F
Pellet
Claire
C
Laroche
Liliane
L
Dubertret
Louis
L
Courtois
Gilles
G
Bachelez
Hervé
H
Michel
Laurence
L
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology; D012751:Sezary Syndrome / Q000209:etiology / Q000473:pathology; D012878:Skin Neoplasms / Q000473:pathology*; D051996:Transcription Factor RelA / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics
D001897:Boronic Acids; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D061988:Proteasome Inhibitors; D011719:Pyrazines; D051996:Transcription Factor RelA; D051028:bcl-2-Associated X Protein; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease