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[Cancer Research 61, 7785-7791, November 1, 2001]
© 2001 American Association for Cancer Research

Biochemistry and Biophysics

Activation of Nuclear Factor {kappa}B through the IKK Complex by the Topoisomerase Poisons SN38 and Doxorubicin

A Brake to Apoptosis in HeLa Human Carcinoma Cells1

Virginie Bottero, Valère Busuttil, Agnès Loubat, Nicolas Magné, Jean-Louis Fischel, Gérard Milano and Jean-François Peyron2

Institut National de la Santé et de la Recherche Médicale U526, Activation des Cellules Hématopoïétiques, Physiologie de la Survie et de la Mort Cellulaires et Infections Virales [V. Bo., V. Bu., J. F. P.] and Institut National de la Santé et de la Recherche Médicale U364, Immunologie Cellulaire et Moléculaire [A. L.], IFR 50 Génétique et Signalisation Moléculaires. Faculté de Médecine Pasteur, 06107 Nice cedex 02, France, and Centre Antoine Lacassagne, Laboratoire d’Oncopharmacologie, 06050 Nice cedex 1, France [N. M., J-L. F., G. M.]

The transcription factor nuclear factor (NF) {kappa}B is involved in the regulation of cell survival. NF{kappa}B is activated in many malignant tumors and seems to play a role in the resistance to cytostatic treatments and escape from apoptosis. We have studied the effects on NF{kappa}B activation of two topoisomerase poisons and DNA damaging agents that are used in chemotherapy: SN38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of CPT11, and doxorubicin. In HeLa cells, both drugs activate NF{kappa}B using a preexisting pathway that requires a functional I{kappa}B-specific kinase complex, I{kappa}B-specific kinase activation, I{kappa}B-{alpha} phosphorylation, and degradation. Blocking NF{kappa}B activation by stable expression of a mutant super-repressor I{kappa}B-{alpha} molecule sensitized HeLa cells to the apoptotic actions of drugs and tumor necrosis factor. RNase protection assay analysis demonstrate that NF{kappa}B is involved in the regulation of a complex pattern of gene activation and repression during the cellular response of HeLa cells to topoisomerase poisons. The blockade of NF-{kappa}B activation seems to shift the death/survival balance toward apoptosis.




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Copyright © 2001 by the American Association for Cancer Research.