Activation of nuclear factor kappaB through the IKK complex by the topoisomerase poisons SN38 and doxorubicin: a brake to apoptosis in HeLa human carcinoma cells
| Autor: | V, Bottero, V, Busuttil, A, Loubat, N, Magné, J L, Fischel, G, Milano, J F, Peyron |
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| Rok vydání: | 2001 |
| Předmět: |
Antibiotics
Antineoplastic Cell Survival NF-kappa B Gene Expression Apoptosis Protein Serine-Threonine Kinases Irinotecan I-kappa B Kinase DNA-Binding Proteins Enzyme Activation NF-KappaB Inhibitor alpha Doxorubicin Humans Topoisomerase II Inhibitors Camptothecin I-kappa B Proteins Cycloheximide Enzyme Inhibitors Phosphorylation Topoisomerase I Inhibitors DNA Damage HeLa Cells |
| Zdroj: | Cancer research. 61(21) |
| ISSN: | 0008-5472 |
| Popis: | The transcription factor nuclear factor (NF) kappaB is involved in the regulation of cell survival. NFkappaB 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 NFkappaB 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 NFkappaB using a preexisting pathway that requires a functional IkappaB-specific kinase complex, IkappaB-specific kinase activation, IkappaB-alpha phosphorylation, and degradation. Blocking NFkappaB activation by stable expression of a mutant super-repressor IkappaB-alpha molecule sensitized HeLa cells to the apoptotic actions of drugs and tumor necrosis factor. RNase protection assay analysis demonstrate that NFkappaB 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-kappaB activation seems to shift the death/survival balance toward apoptosis. |
| Databáze: | OpenAIRE |
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