Lymphoma apoptosis was induced by down-regulating constitutive activation of the nuclear factor-kappa B (NF-kappa B) canonical pathway

07-21-2006

"Constitutive activation of the NF-kappa B 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-kappa B 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 Sezary syndrome (SS) presenting a high ratio of tumor cells, with evidence of p50 and RelA/p65 in DNA-linked complexes," investigators in France reported.

"Transfection of SeAx line with a kappa B/luciferase reporter plasmid showed that translocated NF-kappa B complexes were functional. Selective inhibition of NF-kappa B, by transfecting CTCL cell lines with a super-repressor form of IKB alpha, led to apoptosis. We evidenced down-regulation of NF-kappa B 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-kappa B and induced apoptosis of CTCL cells, with evidence of an upregulation of Bax expression," explained A. Sors and colleagues, INSERM U697.

The researchers concluded, "These results demonstrate the key role played by NF-kappa B 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 and colleagues published their study in Blood (Down-regulating constitutive activation of the NF-kappa B canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis. Blood, 2006;107(6):2354-2363).

For additional information, contact L. Michel, Hopital St. Louis, INSERM, U697, Institute Rech Peau, Pavillon Bazin, 1 Avenue Claude Vellefaux, F-75475 Paris 10, France.